2015 Poster Abstracts

Brandon McKinney
University of Pittsburgh Department of Psychiatry and Translational Neuroscience Program

DNA methylation as a Mechanism for Altered Glutamatergic Signaling in the Superior Temporal Gyrus of Individuals with Schizophrenia

Background: Reduced dendritic spine density on glutamatergic neurons is among the most consistently observed findings in postmortem studies of individuals with schizophrenia (SCZ), affecting multiple brain regions including the superior temporal gyrus (STG). Impaired glutamatergic signaling is believed to underlie dendritic spine loss in the STG and auditory symptoms in individuals with SCZ. We recently showed that proteins that were differentially expressed in the STG of individuals SCZ were enriched in glutamate signaling pathway proteins. Studies in model systems have demonstrated that alterations in DNA methylation (DNAm) alter expression of glutamate signaling pathway proteins. Here, we explore the potential contribution of DNAm alterations to changes in expression of glutamate signaling pathway proteins observed in the STG of individuals with SCZ.

Methods: The Illumina Infinium HumanMethylation450 Beadchip Array was used to quantify genome-wide DNAm in the STG of postmortem brains from 22 individuals with SCZ and 22 age-matched individuals without DSM-IV psychopathology. The normalized Beta values for each CpG site (adjusted for age, sex, and PMI) of duplicate samples were averaged for all subjects within a group and a two-sample t-test between groups was performed and corrections for multiple comparisons made. All subjects used in this study have been extensively characterized with respect to dendritic spine density, synaptic protein expression profile, and polygenic risk for SCZ.

Results: Evidence for multiple sites of differential DNAm between individuals with SCZ and age-matched individuals without DSM-IV psychopathology was found. Among the most significantly altered CpG sites were those in genes that are part of the glutamatergic signaling pathway (e.g., CaMK2Beta). Additional regional analyses of differential DNAm are ongoing.

Conclusions: DNAm may be a mechanism for genome-wide SCZ-related changes in gene and protein expression. Future analysis will explore our a priori hypothesis that these regions of differential methylation are enriched among the genes of the glutamatergic signaling pathway and inversely correlated with expression of proteins in the glutamatergic signaling pathway.”Menachem Fromer
Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai

RNA-sequencing of multiple cortical regions from >500 brains of schizophrenia patients and controls implicates genes overlapping genetic associations and elucidates genetic risk


The most recent schizophrenia GWAS reported >100 associated loci, implying a high degree of polygenicity. To better understand this pathology, the CommonMind Consortium (commonmind.org) is generating large-scale molecular data (RNA-seq, ChIP-seq, DNA-seq/genotyping) from human post-mortem brain samples.


We identify functional changes in gene expression using RNA-seq of 592 samples (258 schizophrenia, 279 controls, and 55 mood disorder) from the dorsolateral prefrontal cortex (DLPFC, BA9/46). For 517 samples, we similarly characterized expression in the anterior cingulate cortex (ACC, BA24/32). Clinical (gender, age of death, ancestry) and technical (brain bank, post-mortem interval, RNA quality, sequencing library batch) covariates, as well as hidden confounders (derived using surrogate variable analysis) were controlled using linear models in voom/limma.


After correction for covariates, a large fraction of the ~16,000 genes analyzed (those with sufficient expression) exhibit differential expression between schizophrenia and controls, 24% of genes in the DLPFC and 20% in the ACC (estimated proportion of non-null hypotheses). We replicated our findings in the DLPFC using microarray expression data in an independent cohort of 449 brain samples (202 schizophrenia, 247 controls) from the NIMH Human Brain Collection Core, with a genome-wide Pearson correlation of r = 0.21 (p < 10-16) between test statistics of differential expression. Taking a cutoff of 5% on estimated FDR for differential expression in the DLPFC yielded a set of 466 genes, which showed significant enrichment relative to all 16,000 genes (p = 0.01, Fisher’s method) for genetic associations with schizophrenia, including common variants and de novo loss of function variants from exome sequencing. Noteworthy among these is the up-regulated gene KCTD13, found in a common variant association locus, but also in the associated 16p11 duplication region.

Combining chip genotypes with DLPFC expression, we identified expression quantitative trait loci (eQTL), finding cis-eQTL (within 1 Mb) for 13,137 genes at FDR < 5% in MatrixEQTL. These eQTL were enriched within 100 kb of the gene, in particular in enhancer sequences derived from brain tissues (p = 4.5 x 10-6) in Roadmap Epigenomics Consortium and ENCODE data. We overlapped these eQTL with the 108 common variant loci associated with schizophrenia to detect genes for which the genetic profile of association with schizophrenia (GWAS) matches association with gene expression (eQTL). Using Sherlock with Bonferroni correction and ensuring correspondence of profiles based on statistical association (p-values) and effect sizes (betas), yielded 11 loci for which only a single gene is implicated. Testing the subset of 9 protein-coding genes, as compared to all ~300 genes with cis-eQTL in the GWAS loci (after excluding the MHC region), for overlap with de novo variation in neuropsychiatric diseases (schizophrenia, autism, and intellectual disability), we found these genes enriched for nonsynonymous de novo mutations in 3,985 probands with autism (fold-enrichment = 3.1, nominal dnenrich p = 0.002, p corrected for multiple testing = 0.015).


This large DLPFC expression dataset is public (http://dx.doi.org/10.7303/syn2759792), and the ACC data will be released in 2016. These resources are facilitating novel discoveries relating neurobiology to disease risk and have the potential to provide novel therapeutic targets.”Christina Hough
Department of Psychiatry, University of California San Francisco

Leukocyte telomere length prospectively predicts SSRI response in major depressive disorder: A preliminary study

Short leukocyte telomere length (LTL) has been associated with several psychiatric disorders, including major depressive disorder (MDD), although conflicting data exist. Short LTL has been associated retrospectively with poor response to psychiatric medications in bipolar disorder and schizophrenia, but no studies have prospectively assessed the relationship of LTL to antidepressant response in MDD. We assessed pre-treatment LTL using qPCR, depression severity using the Hamilton Depression Rating Scale (HDRS), and positive and negative affect using the Positive and Negative Affect Schedule in 27 healthy, unmedicated adults with MDD. Subjects were then treated in an open-label manner with a selective serotonin reuptake inhibitor (SSRI) antidepressant for eight weeks, after which clinical ratings were repeated. Analyses were corrected for age, sex and BMI. “Non-responders” to treatment (HDRS percentage improvement of Thorsten Kranz
New York University

Rare and ultra-rare genetic variants in the neurotrophin signaling pathway are implicated in schizophrenia risk.

Multiple lines of evidence corroborate impaired signaling pathways as relevant to the underpinnings of schizophrenia. There has been an interest in neurotrophins, since they are crucial mediators of neurodevelopment and in synaptic connectivity in the adult brain. Neurotrophins and their receptors demonstrate aberrant expression patterns in cortical areas for schizophrenia cases in comparison to control subjects. There is little known about the contribution of neurotrophin genes in psychiatric disorders. To begin to address this issue, we conducted high-coverage targeted exome capture in a subset of neurotrophin genes in 48 comprehensively characterized cases with schizophrenia-related psychosis. We herein report rare missense polymorphisms and novel missense mutations in neurotrophin receptor signaling pathway genes and specifically, in known protein-protein interaction domains with known function. Furthermore, we observed that several genes have a higher propensity to harbor missense coding variants than others. Based on this initial analysis we suggest that rare variants and missense mutations in neurotrophin genes might represent a risk pathway involved across psychiatric disorders. Michaela Fenckova
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands

Drosophila RNAi-based screen of ~ 300 genes implicated in cognitive disorders using high-throughput measures of synaptic plasticity

Activity-dependent modulation of synaptic strength is a key processes that underlies information processing in the central nervous system and plays an important role in learning and higher cognitive functioning. Deficits in synaptic plasticity have been implicated in several cognitive disorders including Intellectual Disability, Autism Spectrum Disorders (ASD), and Schizophrenia. Simple and evolutionary conserved measures of short-term activity-dependent synaptic plasticity in model organisms are urgently needed to facilitate investigation of the molecular underpinnings of these disorders. We focus on the modulation of the startle response in Drosophila. We performed a pan-neuronal RNAi-based screen of ~ 300 Drosophila gene orthologues most of which are implicated in Intellectual Disability (ID), but also ASD and Schizophrenia. We assessed gene function in two high-throughput paradigms developed by Aktogen Ltd.: (1) habituation, a simple form of non-associative learning that provides an important mechanism for filtering sensory information, and (2) prepulse inhibition, a measure of sensorimotor gating that is affected in a number of neuropsychiatric disorders.
Knockdown of more than one third of the screened genes resulted in impaired (slow) habituation. These genes are enriched for prepulse inhibition deficits, suggesting a mechanistic relationship between these two measures and implying relevance of sensory gating defects to learning and cognition. Moreover, habituation and prepulse inhibition deficits characterize a subgroup of ID genes that is also associated with ASD, making these paradigms attractive for further investigation of ASD–candidate genes. We also show that genes associated with Schizophrenia and with established prepulse inhibition deficit in rodent models lead to disturbed habituation and prepulse inhibition in Drosophila.
We offer Drosophila habituation and prepulse inhibition as relevant paradigms for disease gene validation and mechanistic studies. Established and well-characterized Drosophila habituation and prepulse inhibition models will allow for dissection of molecular pathways and mechanisms, as well as identification of affected neuronal circuits and neurotransmitter systems. The high-throughput nature of our paradigms also bears great potential for large-scale in vivo drug testing and development of treatment strategies.” Brooke Hjelm
Department of Psychiatry and Human Behavior, University of California, Irvine

An mRNA-Seq Signature of Hypoexcitation in Schizophrenia

mRNA sequencing (mRNA-Seq) is a set of methods based upon next-generation sequencing (NGS) technology that allows one to evaluate the transcriptome, effectively providing a snapshot in time of all expressed, polyadenylated transcripts in a diseased (or healthy) tissue sample. We performed mRNA-Seq on postmortem dorsolateral prefrontal cortex (DLPFC) samples from 8 schizophrenia (SZ) subjects and 9 controls (CTRL), and identified a gene transcript signature of cortical hypoexcitation in SZ brains relative to CTRL. Arion et al. previously described a microarray transcriptome profile that correlated with “spiking” (abnormal) and “non-spiking” (normal) cortical areas identified by intraoperative electrocorticography of temporal lobe epilepsy (TLE) patients. Using the gene expression pattern of the “spiking” samples relative to the “non-spiking” (i.e., S-NS) as a model of cortical hyperexcitation, we evaluated this reference list of 72 genes for alterations in SZ pathophysiology. While the majority of these gene transcripts (60/72) were not significantly different between SZ and CTRL brains when compared by Student’s t-tests, rank-order correlation analysis of the relative difference between groups (i.e., SZ-CTRL) demonstrated that the vast majority of this list (53/72) was reversed or inverted. Specifically, Spearman’s correlation tests demonstrated a significant, negative correlation (rho = -0.644, p=6.07e-10) between the “spiking” hyperexcitation gene signature observed in TLE, and the SZ DLPFC samples, suggesting SZ neurons have reduced electrical activity. We have additionally supported this finding of a reduction in the excitatory/inhibitory (E/I) ratio through functional analysis (i.e., electrophysiology) of synaptosomal preparations from the same DLPFC samples. This gene transcript signature of hypoexcitation was further confirmed using publicly available RNA-Seq data from other regions of SZ postmortem brains. Together, these data provide strong evidence that hypoexcitation exists as a pathological feature of SZ, and that alterations in this biological process can be observed by mRNA-Seq analysis and electrophysiology. Abigail Clark
Columbia University

The midline thalamic dopaminergic system modulates anxiety- and fear-related behaviors in mice

The midline thalamus is a key component of the limbic system and pathology in this region has been implicated in numerous psychiatric disorders. In particular, several studies have suggested a decrease in D2 receptors (D2R) in the midline thalamus in schizophrenia. However, little is known regarding the anatomy and function of the midline thalamic dopaminergic system. Using cre-dependent viral tracing techniques in DAT-cre and TH-cre mouse lines, we show that dopaminergic inputs to the midline thalamus arise from both midbrain and hypothalamic dopaminergic regions. Using in situ hybridization and immunohistochemistry, we additionally show that D2R are particularly enriched in the paraventricular nucleus (PVN). With in vitro electrophysiological recordings in D2R-GFP mice, we establish that tonic firing in D2R-expressing cells in the PVN is inhibited by quinpirole and increased by sulpiride. We next probed the function of this system by knocking down D2R in the midline thalamus by use of the inducible GBX2Cre-ERT mouse line, which selectively expresses cre in midline thalamic nuclei. We crossed this line with D2R flx/flx mice and show that knockdown of D2R in the midline thalamus during adulthood leads to increased anxiety, as measured with elevated plus maze, open field test, and light-dark box, as well as increased contextual fear expression 24 hours following fear conditioning. Our findings add to literature suggesting that the PVN is important in the regulation of fear- and anxiety-related behaviors via its connections with the extended amygdala and provides evidence that dopamine within the PVN plays a role in the modulation of these behaviors. Elisa Nabel
Icahn School of Medicine at Mount Sinai

Adolescent Suppression of Prefrontal Nicotinic Signaling Shapes Attention

Attention, the cognitive function that selects task-relevant information, is pervasively impaired in neurodevelopmental disorders and psychiatric illnesses with developmental contributions. Despite this important link, the mechanisms driving development in neural systems mediating attention are poorly understood. Regulatory mechanisms of visual cortex development -the preeminent model for cortical maturation- have been identified in other brain regions and provide a conceptual framework for studying cortical development underlying other functions.
Lynx1, a critical period regulator, spurs cortical maturation in the visual cortex by antagonizing nicotinic acetylcholine receptors (nAChRs). Furthermore, the nACh system is integral to attention processing. In light of this converging evidence, we tested the hypothesis that Lynx1 plays a key role in establishing frontal cortex-dependent attentional function.

We coupled genetic, viral, pharmacological, and histological approaches to behavioral measures of attention using a translational automated touchscreen version of the 5 choice serial reaction time test. We first found that Lynx1 knock-out mice displayed attention deficits in adulthood. This functional deficit was associated with reduced task-dependent-activation of anterior cingulate cortex (ACC) neurons that increasingly express Lynx1 during the peri-adolescence period and throughout adulthood. Viral knockdown of Lynx1 in the ACC from adolescence into adulthood phenocopied the impairment. Strikingly, this attention deficit was rescued by a chronic 10 day pharmacologic nAChR blockade both during peri-adolescent and adult periods –but not by acute blockades during attention testing.

These data suggest that, in the absence of Lynx1, excess nAChR signaling across adolescent development may “freeze” attentional circuit maturation, rendering immature cortical circuits that underlie aberrant frontal cortex activity and long-lasting impairment in attention. Developmental regulation of attentional function by Lynx1 may prove a novel mechanism and therapeutic target for a major cognitive function disturbed in psychiatric disorders with developmental contributions including autism, ADHD, and schizophrenia.” Kevin Spencer
VA Boston Healthcare System/Harvard Medical School

Whole-Brain Analysis of Spontaneous Gamma Activity in Schizophrenia

Recently we reported that spontaneous (non-event locked) gamma power was increased across the gamma band (30-100 Hz) in individuals with schizophrenia (SZ) compared to healthy control subjects (HC) during auditory steady-state stimulation (Hirano et al., 2015, JAMA Psychiatry). This effect was found in the primary auditory cortex, as determined by constructing a spatial filter for auditory cortex activity using dipole source localization of the auditory steady-state response. In the present study we re-analyzed those data to assess the distribution of increased spontaneous gamma activity in schizophrenia throughout the brain, using a distributed source localization method (sLORETA: standardized low resolution tomography).

Subjects were 24 HC and 24 chronic SZ. The samples were matched on age, gender balance, and parental socio-economic status. The EEG was recorded with a dense electrode array (68 scalp electrodes) during passive listening to auditory steady-state stimuli, which were presented in blocks according to frequency (20, 30, and 40 Hz click trains). Artifacts (ocular, saccadic spike potential, electromyographic, and cardiac) were removed with independent component analysis. Spontaneous gamma activity was assessed by measuring total power in the gamma band during the pre-stimulus baseline period (500 ms). Baseline total power was localized with sLORETA to the MNI template brain. Statistical comparisons of HC vs. SZ (2-tailed) were corrected for the number of voxels with permutation testing.

At the whole-brain level, no significant differences were found between HC and SZ in the 20 Hz and 30 Hz stimulation conditions. In the 40 Hz stimulation condition, SZ demonstrated increased power compared to HC in the prefrontal cortex, with the maximum (p < 0.01) located at MNI coordinates [5,40,55] in Brodmann area 8 (superior frontal gyrus). Control analyses using the left and right primary auditory cortices (Brodmann area 41) as regions of interest found similar patterns as our prior results, with significantly increased power in SZ compared to HC overall (p < 0.05), particularly during 40 and 30 Hz stimulation in the left auditory cortex (p’s < 0.05).

The anatomical distribution of increased spontaneous gamma power in schizophrenia during auditory steady-state stimulation depended on the stimulation frequency, being maximal for 40 Hz stimulation in the prefrontal cortex. Thus, increased spontaneous gamma power was not confined to the stimulated sensory cortex, nor was it maximal there. The finding that spontaneous gamma power was greatest in the prefrontal cortex in schizophrenia patients may be consistent with the inhibitory interneuron abnormalities identified there in neuropathological studies. Further research is necessary to understand the factors influencing the strength and anatomical distribution of spontaneous gamma activity in schizophrenia.” Krishna C.
Vadodaria Salk Institute for Biological Studies

Generation of functional human serotonergic neurons

The brain’s serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders1. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro2. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2, LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic neurons from human fibroblasts. Induced serotonergic neurons (iSNs) showed increased expression of specific serotonergic genes that are known to be expressed in raphe nuclei. iSNs displayed spontaneous action potentials, released serotonin in vitro, and functionally responded to selective serotonin reuptake inhibitors (SSRIs). Here, we demonstrate the efficient generation of functional human serotonergic neurons from human fibroblasts as a novel tool for studying human serotonergic neurotransmission in health and disease. Daniel Lindqvist
UCSF/Lund University

Mitochondrial DNA copy number is decreased in unmedicated women with major depression

Introduction: Mitochondrial abnormalities may be involved in Major Depressive Disorder (MDD), although few studies have examined this. Mitochondrial DNA copy number (mtDNA-cn) in leukocytes is an emerging index of mitochondrial biogenesis and function that may relate to psychiatric, as well as somatic symptoms of depression. The present study assessed leukocyte mtDNA-cn in patients with MDD compared to healthy controls as well as its correlation with clinical characteristics.
Methods: Forty-two unmedicated MDD subjects and 54 controls were enrolled in the study. Leukocyte mtDNA-cn was assessed with a TaqMan multiplex assay. Clinical assessments included the Hamilton Depression Rating Scale (HDRS), the Positive and Negative Affect Schedule (PANAS) and the Toronto Alexithymia Scale (TAS). The PANAS and TAS were assessed to explore Research Domain Criteria (RDoC) domains of “Positive Valence”, “Negative Valence” and “Social Processes – Perception and Understanding of Self”.
Results: There were no significant between-group differences in leukocyte mtDNA-cn across all subjects. However, mtDNA-cn was (i) significantly lower in female MDD subjects compared to female controls, but not in male MDD subjects compared to male controls, and (ii), significantly directly correlated with positive affect ratings, and inversely correlated with alexithymia ratings in MDD subjects.
Discussion: This study provides evidence that leukocyte mtDNA-cn is lower in females, but not in males, with MDD. Exploratory analyses suggest that mtDNA-cn was associated with specific RDoC domains in MDD. Characterizing mtDNA-cn, along with mitochondrial biogenesis, function and energy production, may provide a novel window into aspects of MDD pathophysiology.” Eminy Hsiao-Yuan Lee
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

MeCP2 SUMOylation at Lys-412 rescues Mecp2 mutant-induced behavioral deficits in a mouse model of Rett syndrome

The methyl-CpG-binding protein 2 (MeCP2) gene, Mecp2, is an X-linked gene encoding the MeCP2 protein and mutations of Mecp2 cause Rett syndrome (RTT). But the molecular mechanism of Mecp2 mutation-caused RTT is less well known. In this study, we have found that MeCP2 could be SUMO-modified by the E3 ligase protein inhibitor of activated STAT1 (PIAS1) at Lys-412 and MeCP2 SUMOylation is MeCP2 phosphorylation (at Ser-421 and Thr-308)-dependent. MeCP2 SUMOylation is also induced by NMDA, IGF-1 and corticotrophin-releasing factor (CRF) treatments in the hippocampus in vivo. Further, MeCP2 SUMOylation releases CREB from the repressor complex, increases CREB DNA binding to the Bdnf promoter and enhances Bdnf mRNA expression. On the other hand, several Mecp2 mutations identified in RTT patients show decreased level of MeCP2 SUMOylation. Using Mecp2 conditional knockout (cKO) mice as a model for RTT, we have found that overexpression of MeCP2 and SUMOylation of MeCP2 rescue the behavioral deficits of social interaction and cued fear memory performance in Mecp2 cKO mice. Moreover, overexpression of MeCP2 enhances LTP whereas blockade of MeCP2 SUMOylation impairs the expression of LTP. These results together reveal an important role of MeCP2 SUMOylation in social interaction and memory function. We have also identified a novel molecular mechanism for RTT.

Acknowledgments: This work was supported by a Grant from the Ministry of Science and Technology (MOST 103-2320-B-001-004-MY3) and research fund from Institute of Biomedical Sciences, Academia Sinica in Taiwan.” Samuel Clark
Columbia University Medical Center

Multiphoton imaging of novel fluorescent false neurotransmitter AGH270 reveals in vivo dynamics of amphetamine’s effect on individual noradrenergic synapses in murine sensory cortex.

Attention deficit hyperactivity disorder (ADHD) is the most common childhood mental disorder affecting 5% of children in the US. One of the most commonly prescribed first line treatments is amphetamine (administered as Dexedrine or Adderall), a stimulant with both therapeutic effect and a high potential for abuse and addiction. While amphetamine’s potential for abuse is dependent on its action on the dopaminergic synapses of the striatum, it also has potent action at noradrenergic synapses of the cortex. It has been hypothesized that its ability to increase cortical levels of norepinephrine and, indirectly, cortical dopamine through action at the norepinephrine transporter (NET), may underlie much of its therapeutic effects. This is independent of its effects on striatal dopamine levels. We chose primary somatosensory cortex as a model because this area has been shown to be abnormal in children with ADHD, and because cortical noradrenergic synapses comprise an important therapeutic target of the ADHD treatments amphetamine, methylphenidate, and atomoxetine. Amphetamine’s action in the cortex in-vivo has previously only been indirectly observed via SPECT or PET imaging and microdialysis. Here we report the first in vivo optical observation of amphetamine’s action at noradrenergic synapses with single synapse resolution. We utilized in-vivo multiphoton imaging of a norepinephrine specific fluorescent false neurotransmitter (FFN) AGH270 in mice surgically implanted with a cranial window to visualize noradrenergic release from each individual synapse. We either infused or microinjected FFN270 into barrel cortex of wt B6 mice, an area critical for processing sensory perception. We hypothesized that amphetamine would cause vesicular release of NE and that the magnitude of its effect may differ between synapses. We found that in the absence of sensory stimuli, only a small subset of noradrenergic synapses actively released FFN, consistent with phasic activity of the locus coeruleus. However, at 1mg/kg d-amphetamine (i.p.), a mouse dosage equivalent with treatment for ADHD, the FFN was emptied from all synapses within 10 minutes (p=0.005). This is the first in-vivo confirmation that amphetamine can cause vesicular release of NE at treatment relevant doses. The effect was ~2-fold more rapid with 10mg/kg (p=.0002), dosages consistent with amphetamine abuse. Surprisingly, amphetamine’s ability to cause complete release from all synapses was uniform and occurred in the absence of sensory stimulus to the cortex. The effect was blocked by pretreatment with a fluorescent cocaine analogue that acts as a NET inhibitor. This data supports the network reset theory of noradrenergic cortical function and is consistent with an action by which norepinephrine filters cortical neurons to tune out less salient stimuli.
We believe this is both the first time that neurotransmission from individual presynaptic sites and its modulation by amphetamine has been observed in mammalian brain in-vivo. This technique far exceeds the spatial and temporal resolution of either SPECT or PET imaging, and by providing a means to study of individual synapses, elucidates the synaptic mechanisms of noradrenergic drugs.” Dibyadeep Datta
University of Pittsburgh, Departments of Neuroscience and Psychiatry

Dysregulation of ARP2/3 complex in DLPFC deep layer 3 pyramidal cells in schizophrenia

Disturbances in certain cognitive processes, such as working memory, are common in subjects with schizophrenia and have been attributed, at least in part, to dysfunction of the dorsolateral prefrontal cortex (DLPFC). In particular, pyramidal cells, the principal source of cortical glutamate neurotransmission, exhibit morphological alterations in the DLPFC in schizophrenia. These alterations include a smaller somal size, a less complex dendritic arbor and a lower density of dendritic spines. This pattern of pathology is particularly marked in pyramidal neurons located in deep layer 3, and may reflect an intrinsic deficit in the expression of genes that regulate the actin cytoskeleton in these neurons. Consistent with this idea, previous postmortem studies have revealed multiple alterations in expression of genes involved in the cell division cycle 42 (CDC42) signaling pathway, a Rho GTPase signal transduction pathway that is crucial for maintaining dendritic spine structure. In the present study, we examined the potential contribution of the actin-related protein-2/3 (ARP2/3) complex to spine pathology of DLPFC deep layer 3 pyramidal neurons in schizophrenia. We focused on the ARP2/3 complex because it 1) serves as a molecular hub downstream of the CDC42 pathway, and 2) is related to genetic risk factors for schizophrenia that regulate actin cytoskeleton dynamics. Individual pyramidal cells (200 cells/subject) in DLPFC deep layer 3 were captured using laser microdissection from 36 matched pairs of schizophrenia and healthy comparison subjects. Total RNA was isolated and levels of transcripts for the ARP2/3 complex subunits (ACTR2, ACTR3, ARPC1, ARPC2, ARPC3, ARPC4 and ARPC5) were quantified using microarray. The mRNA expression of the ATP-binding component of the complex were significantly lower (ACTR2, -10.9%, p=0.001; ACTR3, -15.2%, p Jacqueline Kulbe
University of Kentucky Spinal Cord and Brain Injury Research Center

Temporal profile of non-synaptic and synaptic mitochondrial bioenergetics following severe controlled cortical impact traumatic brain injury in rats.

Traumatic brain injury (TBI) results in a multitude of morbidities including psychiatric, emotional, cognitive and motor dysfunction. Neurodegeneration and synaptic dysregulation contribute greatly to these morbidities. Following injury, Ca++ is sequestered by mitochondria in an attempt to maintain homeostasis. However, the mitochondria become stressed, resulting in increased production of reactive oxygen and nitrogen species. These reactive species initiate lipid peroxidation (LP), leading to the formation of neurotoxic aldehydic LP breakdown products, 4-HNE and acrolein, which cause mitochondrial oxidative damage. This leads to decreased bioenergetics and mitochondrial permeability transition (MPT). Ca++ is released back into the cytosol, leading to cytoskeletal degradation and neurodegeneration. The temporal profile of non-synaptic and synaptic mitochondrial populations following TBI in the rat has not been studied. Here we show that following severe controlled cortical impact (CCI) TBI, synaptic mitochondria respiratory dysfunction begins as early as 3h following injury, and continues to decrease for at least 48h. However, non-synaptic mitochondria respiratory function is not significantly decreased until 48h. Additionally, 48h following injury the respiratory function of synaptic mitochondria is significantly decreased compared to the non-synaptic population. Interestingly, 48h correlates with increases in total mitochondrial oxidative damage. These findings show that compared to the non-synaptic population, synaptic mitochondria are more susceptible to larger and earlier decreases in respiratory function. Our goal is to develop pharmacotherapies to protect both mitochondrial populations. We are currently investigating two FDA-approved drugs, the immunosuppressant cyclosporine A (CsA) which inhibits MPT, and the MAO inhibitor phenelzine which is capable of scavenging neurotoxic aldehydes.[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Dustin B. Stephens
University of Kentucky Department of Psychiatry & Eastern State Hospital

CYP2D6 Ultrarapid Metabolizer Phenotype Not Associated with Attempted Suicide in a Large Sample of Psychiatric Inpatients

Suicide accounts for more than 41,000 deaths annually in the United States and is the 10th-leading cause of mortality. Multiple studies have investigated potential association between the cytochrome P450 CYP2D6 ultrarapid metabolizer (UM) phenotype and suicidality. Thus far mixed results have been reported in these studies, although the majority have examined relatively small, restricted samples without analysis of statistical power. This project examined 4264 psychiatric inpatients recruited from 2004-2006 in order to test the hypothesis of increased risk of suicidal behavior among UMs. 2435 (57%) of these individuals reported at least one prior suicide attempt with serious intent. No association between UM phenotype and suicidality was revealed in univariate (OR=0.87, 95% confidence interval [CI]: 0.53-1.25; p=0.59), risk-stratified (e.g. among patients with any primary mood disorder: OR=0.57, 95% CI: 0.26-1.25; p=0.16), or multivariate analyses adjusting for potential confounding variables (adjusted OR=0.89, 95% CI: 0.55-1.46; p=0.65). These results argue against previous reports of heightened risk of suicidal behavior among CYP2D6 UMs and highlight the pressing need for developing effective methods of risk stratification and intervention to address this persistent public health problem.[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Zachary Lorsch
Icahn School of Medicine at Mount Sinai

Network-based transcriptional profiling in mice resilient to chronic social defeat stress

Major Depressive Disorder (MDD) causes significant morbidity and mortality worldwide, yet the molecular basis of depression is not well understood. Consequently, development of targeted antidepressants has been limited and a large portion of MDD patients fail to respond to currently available therapeutics. Animal models of MDD, such as chronic social defeat stress (CSDS) in mice, have been successful in identifying molecular determinants of susceptibility and resilience to stress, but experiments to date have primarily focused on single genes and biochemical pathways. While network-based studies of MDD exist, no network-wide experiments have examined the antidepressant homeostatic changes in the resilient phenotype in CSDS. In this study, we performed differential expression and Weighted Gene Co-Expression Network Analysis on transcriptional profiles obtained from key depression-related brain regions (nucleus accumbens, prefrontal cortex, basolateral amygdala, and ventral hippocampus) in resilient mice following 10-day of CSDS. Using this approach, we identified seven gene networks that show differential connectivity between mice resilient to CSDS and mice susceptible to CSDS. Four of these networks are also enriched for genes differentially expressed between resilient and susceptible mice, indicating specificity to the resilient phenotype. For all of these four networks, we have characterized highly connected key driver genes, many of which are also resilient-specific. Additionally, for one of these networks, we have identified Creb an upstream gene that may act as a putative master-regulator of resilience to CSDS.[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Daniel Kashima
Vanderbilt University

Examining the role of toll-like receptor 4 on nucleus accumbens synaptic physiology and drug reward behavior

Drug abuse and addiction remain significant problems in society. Drugs of abuse alter the nucleus accumbens (NAc) physiology suggesting it plays a role in a final common pathway for dependence/addiction. The NAc is made up of two types of medium spiny projection neurons (MSNs) that differentially modulate reward behavior. Neuron-mediated mechanisms of change at excitatory synapses within the NAc in response to drug experience are well-studied. However, growing evidence suggests the involvement of the brain’s innate immune system in modulating reward behavior and synaptic physiology. Previous studies demonstrated that pharmacologic manipulation of toll-like receptor 4 (TLR4), a pattern-recognition molecule of the innate immune system, attenuates cocaine-reward learning. In the brain, TLR4 is primarily associated with microglia. Microglia are phagocytes with the ability to regulate synaptic physiology through 1) physical removal of synapses during development, 2) responses to certain forms of injury, and 3) secretion of chemical factors known to mediate homeostatic plasticity. Despite these observations, mechanistic examination of how the innate immune system alters NAc synaptic physiology in relation to drug-reward behavior has not been pursued. We performed behavioral assays as well as cell-type specific electrophysiology on wild type and TLR4 knockout mice.

We show that TLR4 knockout mice exhibit an attenuation in cocaine-mediated reward learning. Additionally, we find that these mice exhibit altered synaptic properties and plasticity in the NAc. These results suggest that TLR4 and the immune system may directly affect synaptic physiology to alter reward behavior.”[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Angela Ianni
NIH/University of Oxford

Dopamine Synthesis and Receptor Profile Are Associated with Body Mass Index in Humans

Obesity is a worldwide epidemic with significant adverse health consequences such as diabetes, cardiovascular disease, hypertension, and stroke. While behavior clearly plays an important role, the neurobiological underpinnings of weight control require further delineation in humans. Dysfunction of the mesolimbic dopamine system, which mediates the rewarding effects of appetitive stimuli such as food, has been implicated in the development of obesity (1,2). Furthermore, striatal D2 receptor levels are decreased in obese individuals (3) and inversely correlated with future weight gain and food seeking-behavior in rats (2). However, no studies to date have assessed the roles of both dopamine synthesis and receptor density in healthy humans in the normal to obese range. Characterizing the dopaminergic signature related to higher body mass index (BMI) could provide insight into an important neural mechanism underlying the obesity epidemic.

Seventy one healthy volunteers (mean age 35.7, range 18.7-58.6; mean BMI 25.6, range 17.8-36.1; 32 females) were recruited from the local community and screened by physician-administered physical examination, neurological examination, standardized clinical interview (SCID-IV), laboratory tests, and structural MRI read by a radiologist to rule out history of or current psychiatric, neurological, or major medical illness, as well as substance abuse or current medications that could affect the PET measurements. Subjects completed three PET scans on separate days to assess dopamine presynaptic synthesis capacity (with [18F]DOPA on a GE Advance scanner), and D1 and D2 receptor binding potential (with [11C]NNC112 and [18F]Fallypride, respectively on a Seimens HRRT scanner). Following a transmission scan, dynamically binned emission scans were collected for 4 hours (Fallypride) and 1.5 hours (FDOPA and NNC) after tracer injection. Caffeine and nicotine were restricted for four hours and food (for FDOPA only) for six hours before the scan, and subjects were pretreated with carbidopa 200 mg one hour prior to injection for the FDOPA scan to reduce peripheral metabolism of the tracer. BMI was calculated using height and weight measurements taken by nursing staff typically on the same day as the PET scan (an average of 15+77 days from the PET scan). In addition, for forty four subjects, BMI had also been measured an average of 1.6±0.7 years prior to the PET scan, and this earlier value, in comparison to the more current value, was used to calculate a rate of BMI change.
Subjects also completed a T1-weighted MRI scan used for registration and brain segmentation. MRI scans were segmented using Freesurfer and manual adjustments to generate ROIs of the basal ganglia including the putamen, caudate nucleus, ventral striatum, and midbrain. MRI images were registered to native space PET images and values were extracted for each of the ROIs. The FDOPA uptake rate (Ki) was calculated with the Patlak method and dopamine receptor D1 and D2 receptor binding potential were calculated with the SRTM method, both using a cerebellar reference region. Correlations between BMI and PET ROI values were assessed in SPSS, with a threshold of p”[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Rodrigo Pacifico
The Scripps Research Institute – FL

The human striatum transcriptome in bipolar disorder

Estimates of heritability for bipolar disorder (BD) are high, but genome-wide association studies have had limited success in identifying single genes that are strongly associated with the disorder—reinforcing the notion that its etiology is complex and heterogeneous. Additionally, many genetic variants identified by such studies lie on intergenic and intronic regions, suggestive of effects on gene expression. Although postmortem transcriptomic studies of BD have mainly focused on cortical brain regions, the impulsive and risk-taking behavior often seen in manic patients suggests that striatal dysfunction could also be involved in the pathophysiology of BD. Therefore, we profiled the transcriptome of the human dorsal striatum via total RNA sequencing, comparing 18 BD and 17 control postmortem samples. Fourteen genes were found to be differentially expressed between the two groups at a 5% false-discovery rate. Additionally, functional enrichment analysis found an overall increase in expression of immune/inflammation genes in the BD group, as well as a decrease in expression of genes from energy metabolism pathways. Furthermore, two modules identified by co-expression network analysis were found to be enriched in BD susceptibility SNPs. The module with the strongest genetic association signal was comprised mostly of genes involved in signaling pathways. Strikingly, this particular module was also found to be highly specific to the striatum and to medium spiny neurons based on enrichment of regional and cell-type markers—unlike most other modules, which showed no such specificity. These findings reveal a molecular link between BD and a specific brain region, and suggest that genetic variants affecting signaling pathways in striatal medium spiny neurons may be particularly important in the etiology of the disorder.[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Joy Lin
UCSF School of Medicine

Associations of Inflammation with objective and subjective measures of social relationships in patients with and without PTSD

Previous research has linked different indicators of social relationships with poor health outcomes. Social isolation and social integration reflect objective measures of social network size, while perceived social support measures index subjective perceptions of support available from family, friends, and significant others. Both social isolation and low perceived support may be risk factors for elevated inflammation and subsequent morbidity and mortality. We examined associations of objective and subjective measures of social relationships with inflammation. Our sample included 745 Veterans Affairs outpatients from the Mind Your Heart Study (mean age = 58 ± 11; 94% male). Social isolation was assessed using the Berkman Syme Social Network Index (SNI); low perceived support with the Multidimensional Scale of Perceived Social Support (MSPSS); and inflammation with high sensitivity C-reactive protein (hsCRP), white blood cell (WBC) count, and fibrinogen. Posttraumatic stress disorder (PTSD) was assessed with the Clinician Administered PTSD Scale and 35% of the sample had a current diagnosis of PTSD. Hierarchical linear regression was used to examine associations of objective and subjective measures of social relationships with inflammation. Bootstrapped models were used to examine the interactive effect of social relationships and PTSD on inflammation. All models were adjusted for age and gender. In our sample, social isolation was associated with elevated WBC count (β = -0.08, p = 0.03). On the other hand, low perceived support was not associated with any inflammatory marker. Social isolation was significantly associated with all inflammatory markers among individuals without PTSD (β = -0.12, p = 0.01 for hsCRP; β = -0.14, p = 0.003 for WBC count; β = -0.12, p = 0.01 for fibrinogen), but was not associated with any inflammatory markers in those with PTSD (β = 0.04, p = 0.51 for hsCRP; β = 0.04, p = 0.57 for WBC count, β = 0.02, p = 0.71 for fibrinogen). Our findings show that inflammation is more strongly associated with objective rather than subjective measures of social support. It is possible that interventions that increase levels of social integration could reduce inflammation in individuals without PTSD, whereas further research is necessary to clarify the lack of association between social integration and inflammation in those with PTSD.[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Samuel Ridout
Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI

Depression and Telomere Length: A Meta-Analysis

Background: Several recent studies have investigated the relationship between telomere length and depression with inconsistent results. This meta-analysis examined whether telomere length and depression are associated and, using subgroup analyses, explored factors that might affect this association.
Methods: Studies measuring telomere length in subjects meeting interview or rating scale thresholds for clinically significant unipolar depression were included. A comprehensive electronic search strategy identified studies in PubMed, MEDLINE, PsycINFO, Global Health, The Cochrane Library, and Web of Science. A structured data abstraction form was used and studies were appraised for inclusion or exclusion using a priori conditions. Analyses were conducted using standardized mean differences (SMDs) in a continuous random effects model.
Results: Thirty-seven studies (N = 34,347) met the inclusion criteria. Overall, there was a significant association between depression and telomere length, with a Cohen’s d effect size of -0.205 (p < 0.0001, I2 = 42%). Depression severity significantly associated with telomere length (p = 0.03). Trim and fill analysis indicated the presence of publication bias (p = 0.003), but that the association remained highly significant after accounting for the bias. Subgroup analysis revealed depression assessment tools, telomere measurement techniques, source tissue and comorbid medical conditions significantly affected the relationship.
Conclusions: The results show an association between depression and telomere length. Further studies are needed to clarify the direction of causality underlying this association and to elucidate the biology linking depression and this cellular marker of stress exposure and aging.”[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Kathryn Ridout
Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University

Childhood Maltreatment and Methylation of FKBP5

Background: A growing body of evidence suggests that alterations in the stress response system may be a mechanism by which childhood maltreatment alters risk for psychopathology. FK506 binding protein 51 (FKBP5) binds to the glucocorticoid receptor and alters its ability to respond to stress signaling. Previous work has shown that methylation of the FKBP5 gene (FKBP5) at intron 7 is decreased in adults with a history of childhood maltreatment and that a genetic variant of FKBP5 affects the degree of methylation. Decreased FKBP5 intron 7 methylation is associated with increased glucocorticoid induction of FKBP5 expression and decreased glucocorticoid receptor sensitivity. Studies of subjects with later traumas did not exhibit FKBP5 methylation changes, suggesting a role of developmental stage at the time of exposure in FKBP5 methylation. The aim of the present study was to examine the impact of childhood maltreatment and an FKBP5 genetic variant on FKBP5 methylation in a sample of impoverished preschool-aged children. This is the first study to specifically examine FKBP5 epigenetic changes with maltreatment exposure in this age group.

Methods: One hundred seventy-four families, including n=69 with child welfare documentation of moderate-severe maltreatment in the past six months, participated in this study. Families of children with no indicated case of maltreatment within the past six months served as the control group. Children ranged in age from 3 to 5 years, and were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors, and a composite variable assessed the number of exposures to these adversities. Methylation of FKBP5 intron 7 CpG sites was measured from saliva samples via sodium bisulfite pyrosequencing.

Results: Maltreated children had lower levels of methylation at intron 7 FKBP5 CpG sites (p”[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Vineet Tiruvadi
Emory University School of Medicine

Cortico-limbic Network Dynamics in Deep Brain Stimulation for Depression

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) white matter tracts is a promising therapeutic strategy for treatment resistant depression (TRD). Despite growing investigational use of SCC DBS, its effects on signaling within brain networks has not been sufficiently modeled, leading to inconsistent implementation. Here, we report on preliminary brain recordings from a novel neurostimulator capable of simultaneous stimulation and recording of local field potentials (LFPs). LFPs are collected in conjunction with 256-channel EEG in TRD patients treated with SCC DBS. We find synchronous oscillatory activity locked to stimulation onset, with time-frequency domain features that differentiate stimulation conditions and location. In addition, we find stimulation-locked changes in specific EEG channels over regions known to be connected through SCC white matter tracts. Finally, we propose an approach to develop a generative model that can be used to test hypothesized DBS effects in a Bayesian framework. This work is an important step in developing a quantitative model of dysfunctional network signaling in TRD and improving SCC DBS implementation and design.[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Mary Youssef
Columbia University Medical Center

Transient reduction in neurogenesis during the early postnatal period decreases adult dentate gyrus neurogenesis

Early life stress has been shown to increase vulnerability to psychiatric illness in adulthood. The stress response is complex and leads to many changes in the brain that could later increase susceptibility to disease. The hippocampal dentate gyrus (DG), one of the two brain regions in which lifelong neurogenesis occurs, is altered by stress and plays a role in stress regulation. In this study, we sought to determine whether inhibition of neurogenesis during critical developmental periods, as would occur during stress exposure, has a permanent effect on DG neurogenesis throughout life. We transiently decreased cell proliferation during the early postnatal and pre-adolescent periods by treating GFAP-Tk mice with valgancyclovir, then assessed levels of DG neurogenesis in adulthood using Nestin lineage tracing. We found that reversible inhibition of neurogenesis during the early postnatal period leads to fewer doublecortin and NeuN positive neurons from the Nestin lineage, suggesting that the early postnatal intervention leads to a permanent reduction in neurogenesis throughout life. On the other hand, reversible inhibition during the pre-adolescent period does not affect the total number of adult born immature or mature neurons from the Nestin lineage, suggesting that neurogenesis recovers after this intervention. This study highlights the early postnatal period as a sensitive period during which perturbations to neurogenesis, as potentially caused by stress, can alter the lifelong set point for neurogenesis. These results may have implications for the way we approach early life stressors in relation to psychiatric illness.[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Christopher Mazzone
University of North Carolina at Chapel Hill

Pharmacogenetic dissection of Gq-mediated effects on anxiety, cardiac function, and network metabolic activity within the bed nucleus of the stria terminalis

The bed nucleus of the stria terminalis (BNST) is associated with regulating anxiety-related behavior in both humans and rodents. Recent studies show that both anxiety and associated autonomic activity can be differentially regulated through distinct BNST output nuclei, however the involvement of discrete cell subpopulations and signaling pathways has not been described. Here we investigate how engagement of endogenous signaling cascades in GABAergic BNST VGAT neurons can modulate anxiety-related behavior and downstream circuit function. We show that stimulation of BNST VGAT neurons using hM3Dq Designer Receptors Exclusively Activated by a Designer Drug (DREADDs) promotes anxiety-like behavior in a manner independent of changes in heart rate. Further, we used DREADD-assisted metabolic mapping (DREAMM) to profile brainwide network activity following activation of Gq-mediated signaling in BNST VGAT neurons and saw increased activity within ventral midbrain structures including the ventral tegmental area and hindbrain structures such as the locus coeruleus and parabrachial nucleus. These results highlight how Gq-mediated signaling in BNST VGAT neurons can drive downstream network activity that correlates with anxiety-like behavior and points to the importance of identifying endogenous G-protein coupled receptors within genetically defined cell populations. To accomplish this, we isolated BNST VGAT neurons and performed single-cell qPCR using probes targeting known Gq-coupled receptors. Together these results provide a novel single-cell profile of receptors within BNST VGAT neurons that may serve as therapeutic targets for regulating anxiety states.[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Daniel Chung
University of Pittsburgh, Department of Psychiatry, Translational Neuroscience Program

Reduced cortical excitatory inputs onto parvalbumin-positive interneurons in schizophrenia

Impaired gamma oscillations and working memory deficits in schizophrenia are thought to be due, at least in part, to reduced activity of parvalbumin (PV)-positive interneurons in the dorsolateral prefrontal cortex (DLPFC). Studies from animal models indicate that the reduced activity of parvalbumin interneurons in schizophrenia may reflect impaired formation of cortical excitatory inputs onto these cells. Therefore, we hypothesized that the density of cortical excitatory inputs onto parvalbumin interneurons is lower in the DLPFC of subjects with schizophrenia.

Sections containing DLPFC area 9 from 20 pairs of subjects with schizophrenia and healthy comparison subjects were processed for fluorescent immunohistochemistry using antibodies for PV, VGlut1 and PSD95. VGlut1 and PSD95 were used to identify pre- and postsynaptic excitatory terminals, respectively. 10 randomly sampled sites in layer 4 from each section were imaged under Olympus DSU spinning disk confocal microscope with a 60X 1.42 NA oil immersion objective. Images were deconvolved and masked to define the cell bodies of PV interneurons and VGlut1+ and PSD95+ puncta. Number of VGlut1+/PSD95+ puncta per surface area of PV cell body was calculated.

Levels of PV immunoreactivity was 34% lower in PV cell bodies in subjects with schizophrenia. Density of VGlut1+/PSD95+ puncta onto the cell body of PV interneurons was 18% lower in subjects with schizophrenia. Density of total VGlut1+/PSD95+ puncta per image did not differ between subject groups. Somal levels of PV immunoreactivity were positively correlated with the density of VGlut1+/PSD95 puncta onto PV interneurons.

As the levels of PV immunoreactivity reflect PV interneuron activity, our findings provide evidence of fewer cortical excitatory inputs preferentially onto PV interneurons, which would consequently result in lower PV interneuron activity in patients with schizophrenia.”[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Adriana Ramos Amigo
Johns Hopkins University

GAPDH stress pathway and cellular autofluorescence: novel mechanisms involved in cognitive deficits in SCZ

BACKGROUND: Recent studies with SZ patients and animal models have highlighted that excess oxidative stress may play a role in the pathology of the disease, in particular the progression of the disease. On the other hand, Glyceraldehyde-3-phospate Dehydrogenase (GAPDH) can act as a sensor of oxidative stress: our group has reported that under stress a small fraction of GAPDH is posttranslational modified and translocated to non cytosolic fractions to mediate stress signaling (which we call the “GAPDH stress pathway”). We have recently showed that this pathway is activated in rodent models that display behavioral and cognitive deficits relevant to SZ (Johnson et al. Proc Natl Acad Sci USA. 2013). These data suggest a role for the “GAPDH stress pathway” in the pathology of SZ. For that reason we propose this pathway could play a central role to find a mechanism-guided biomarker for SZ.

METHODS: LPS treatment. Mice were daily administrated with LPS 0.1 mg/Kg/day intraperitoneally for four days; (1R, 3R)-1,3-dymethyl-2-propargyl-1,2,3,4 tetrahidrosiquinoline, (RR) treatment. Mice were daily administrated with RR 1.25mg/kg/day intraperitoneally for 5 weeks. Cells were treated with 100 nM RR. Recruitment and clinical evaluations, chronic SZ patients and subjects with first episode of psychosis were recruited in Johns Hopkins Schizophrenia center and Zucker Hillside hospital. Psychiatric symptoms were evaluated with the Scales for the Assesment of Positive Symptoms (SAPS) and the Assesment of Negative Symptoms (SANS). Cognitive function was assessed by a battery of neuropsychological tests, which covered 6 cognitive domains; Autofluorescence (AF), cell suspensions were subjected to flow cytometry detecting signals in the 530±15 nm range after excitation by 488 nm light with the BD FACSCaliburTM.

RESULTS: We explored the role of GAPDH stress pathway in neurocircuitry and behavioral abnormalities relevant to cognitive deficits in SZ, by utilizing animal models. LPS treated and DN-DISC1 mice showed an increase of GAPDH-Siah1 (GAPDH and Siah1 protein interaction reflects the extent of the “GAPDH stress pathway”) binding in cortex. We found this increase was specifically happening in microglia cells in the LPS treated animals.
We have recently developed a novel compound that blocks GAPDH-Siah1 binding with high specificity [(1R, 3R)-1,3-dymethyl-2-propargyl-1,2,3,4-tetrahidrosiquinoline (RR).The application of this compound (RR) ameliorated the cognitive defects in Dominant-negative DISC1 animals.
As we want to be able to detect the activation of this pathway in a high-throughput manner, we checked for other possible markers. Interstingly, we found an increase of autofluorescence in PBMCs from LPS treated animals.
After our preliminary results in animals, we explored AF as a possible biomarker in humans. Therefore, we examined lymphoblasts (LB) from SZ, and we found an augmentation of cellular AF in LB from these patients in comparison with their matched controls. Age, race, gender, and medication do not affect the levels of AF. Importantly, the levels of AF are negatively correlated with cognitive deficits, specifically with executive function, but not with positive and negative symptoms. The RR compound also reduced the higher levels of AF due to oxidative stress in human LB.

CONCLUSION: The major goal of our study is to validate a pivotal role of the “GAPDH stress pathway” in SZ pathology (in particular in association with cognitive deficits) by using patient cells. We also hope that the measurement of AF may be a potential, high-throughput biomarker for SZ. Also, we are exploring how this molecular pathway is involved in neurocircuitry and behavioral abnormalities relevant to cognitive deficits in SZ, by utilizing animal models.”[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Maju Koola Sheppard
Pratt Health System, Baltimore, MD and Department of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

Kynurenine Pathway and Cognitive Impairments in Schizophrenia: Pharmacogenetics of Galantamine and Memantine

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia, identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the α7 nicotinic receptors. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. There is evidence to suggest that the combination of galantamine and memantine may be effective in the treatment of cognitive impairments in schizophrenia. Preliminary data with this combination showed an improvement in five out of seven MATRICS Consensus Cognitive Battery (MCCB) domains. There is a growing body of evidence that excess kynurenic acid (KYNA) is associated with cognitive impairments in schizophrenia. The α-7 nicotinic and the NMDA receptors may counteract the effects of kynurenic acid (KYNA) resulting in cognitive enhancement. Galantamine and memantine through its α-7 nicotinic and NMDA receptors respectively may counteract the effects of KYNA thereby improving cognitive impairments. Cholinergic Receptor, Nicotinic, Alpha 7 gene (CHRNA7 gene), rs2275163, rs904952, rs6923492, rs1053230 may predict treatment response to galantamine and memantine combination to cognitive impairments in schizophrenia in the kynurenine pathway.[/vc_column_text][vc_separator border_width=”4″][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]Maarten van den Buuse
La Trobe University, School of Psychology and Public Health, Melbourne, Australia

BDNF Val66Met Genotype Recapitulates PTSD-Related Endophenotypes via Sensitivity to Stress Hormones in Adolescence

Brain-Derived Neurotrophic Factor (BDNF) is a promoter of neuronal plasticity. The BDNF gene Val66Met polymorphism disrupts activity-dependent secretion of BDNF and has been associated with Post-Traumatic Stress Disorder (PTSD). However, despite being a requisite etiological factor, it has not yet been assessed whether prior stress exposure determines the expression or persistence of fear in Val66Met carriers. We therefore sought to model the long-term effects of chronic stress by using a novel Val66Met knock-in mouse that is genetically modified to express human BDNF (hBDNF) via endogenous mouse promoters. To simulate stress, corticosterone (CORT) was administered in the water of wild-type (hBDNFVal/Val) and mutant (hBDNFMet/Met) mice at a dose of 25mg/L from 6 to 9 weeks of age (adolescence). Following a two week wash-out period mice underwent behavioural testing and were screened for differences in spatial memory on the Y-Maze, memory of fear and extinction learning. At baseline, memory of contextual fear was disrupted in hBDNFMet/Met mice relative to hBDNFVal/Val controls, but was rescued by a BDNF-CORT interaction which selectively enhanced the memory of hBDNFMet/Met mice. A similar phenotype was also observed on the Y-Maze, where hBDNFMet/Met mice showed a lack of preference for the novel arm over the other arms, but was reinstated to levels consistent with controls following the chronic CORT treatment. While extinction learning was unaffected in male and female hBDNFMet/Met mice at baseline, chronic CORT attenuated extinction learning selectively amongst female hBDNFMet/Met mice during the late-phase of extinction trials. In summary, we report that chronic CORT exposure interacts with the BDNF Val66Met polymorphism to selectively modify the expression and extinction of fear. This novel gene-environment interaction highlights how fear is regulated by both BDNF and CORT exposure, having implications for the treatment and prevention of stress-inducible psychiatric disorders such as PTSD. Sex differences found in this study provide mechanistic support for the predominance of PTSD in females, and recapitulates preliminary clinical evidence that the BDNF Val66Met polymorphism is a risk factor for this disorder. 


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