In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in c-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex-and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD 67 ) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA A receptor subunits (a1, a4, b3, c2 and d). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD 67 , SST and a1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCKcontaining subpopulations of GABA neurons and in the signaling via certain GABA A receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.

Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss (1). Clinical and pre-clinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions (2-9), but the molecular mechanisms underlying these morphological alterations have not yet been identified. Here, we show that stress increases levels of REDD1 (regulated in development and DNA damage responses 1), an inhibitor of mTORC1 (mammalian/mechanistic target of rapamycin complex 1) (10), in rat prefrontal cortex (PFC). This is concurrent with a decrease in phosphorylation of signaling targets of mTORC1, which is implicated in protein synthesis-dependent synaptic plasticity. We also found that REDD1 levels are increased in the postmortem PFC of human subjects with MDD relative to matched controls. Mutant mice with a deletion of REDD1 are resilient to the behavioral, synaptic, and mTORC1 signaling deficits caused by chronic unpredictable stress (CUS), while viral-mediated over expression of REDD1 in the rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and pre-clinical findings identify REDD1 as a critical mediator underlying the atrophy of neurons and depressive behavior caused by chronic stress exposure.

Evidence continues to build suggesting that the GABAergic neurotransmitter system is altered in brains of patients with major depressive disorder. However, there is little information available related to the extent of these changes or the potential mechanisms associated with these alterations. As stress is a well-established precipitant to depressive episodes, we sought to explore the impact of chronic stress on GABAergic interneurons. Using western blot analyses and quantitative real-time PCR (qPCR) we assessed the effects of five-weeks of chronic unpredictable stress (CUS) exposure on the expression of GABA-synthesizing enzymes (GAD65 and GAD67), calcium-binding proteins (calbindin (CB), parvalbumin (PV) and calretinin (CR)), and neuropeptides co-expressed in GABAergic neurons (somatostatin (SST), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and cholecystokinin (CCK)) in the prefrontal cortex (PFC) and hippocampus (HPC) of rats. We also investigated the effects of corticosterone (CORT) and dexamethasone (DEX) exposure on these markers in vitro in primary cortical and hippocampal cultures. We found that CUS induced significant reductions of GAD67 protein levels in both the PFC and HPC of CUS-exposed rats, but did not detect changes in GAD65 protein expression. Similar protein expression changes were found in vitro in cortical neurons. In addition, our results provide clear evidence of reduced markers of interneuron population(s), namely SST and NPY, in the PFC, suggesting these cell types may be selectively vulnerable to chronic stress. Together, this work highlights that chronic stress induces regional and cell type-selective effects on GABAergic interneurons in rats. These findings provide additional supporting evidence that stress-induced GABA neuron dysfunction and cell vulnerability play critical roles in the pathophysiology of stress-related illnesses, including major depressive disorder.

Objective-Cognitive impairments in schizophrenia are associated with lower expression of markers of γ-aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABA A receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABA A receptor α4 and δ subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia.Method-The authors used in situ hybridization to quantify expression patterns of GABA A receptor α4 and δ subunits in pre-frontal cortex from 23 matched pairs of schizophrenia and comparison subjects.Results-Levels of δ mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas α4 mRNA levels were lower only in subjects with schizophrenia receiving certain medications at the time of death. To understand the nature of this unexpected dissociation between α 4 and δ subunit expression in schizophrenia, the authors used similar methods to quantify α4 and δ mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of α4 mRNA decreased, whereas δ mRNA levels increased. In addition, δ mRNA levels, but not α4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABA A receptor α1 subunit, and neither δ nor α4 mRNA levels were altered in rodent models of altered excitatory neurotransmission.Conclusions-Since GABA A receptor α1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with δ subunits to form functional GABA A receptors, lower δ mRNA levels in schizophrenia might reflect a reduced number of α 1 β x δ GABA A receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.Deficits in certain cognitive functions, such as working memory, are core features of schizophrenia (1). Alterations in the inhibitory circuitry of the dorsolateral pre-frontal cortex may contribute to the impairments in working memory since optimal levels of γ-aminobutyric acid (GABA) neurotransmission in this cortical region are essential for normal working memory performance (2,3). Consistent with this idea, postmortem studies have consistently shown lower expression of the mRNA for the 67-kDa isoform of glutamate decarboxylase (GAD 67 ), the principal enzyme responsible for the synthesis of GABA, and for the GABA NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript membrane transporter 1 (GAT-1), in the dorsolateral prefrontal cortex of subjects with schizophrenia (see reference 4 for a review).Understanding the functional significance of these pre-synaptic alterations requires knowledge of the expression levels of postsynaptic GABA A receptors. GABA A receptors are ligand-gated chloride ion channels assembled from different subunit classes that most commonly include 2α, 2β, and 1γ or 1δ subunits (5). Different combinations of subunits form GABA A rec...

Circulating triglycerides (TG) normally increase after a meal but are altered in pathophysiological conditions such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason, and because consumption of high fat diet alters dopamine signaling, we tested the hypothesis that TG might directly target mesolimbic reward circuits to control reward-seeking behaviors. We found that the delivery of small amounts of TG to the brain through the carotid artery rapidly reduced both spontaneous and amphetamine-induced locomotion, abolished preference for palatable food, and reduced the motivation to engage in food-seeking behavior. Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food seeking behavior. Finally, prolonged TG perfusion resulted in a return to normal palatable food preference despite continued locomotor suppression, suggesting that adaptive mechanisms occur. These findings reveal new mechanisms by which dietary fat may alter mesolimbic circuit function and reward seeking.