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Journal ArticleDOI

Changes in the Prefrontal Glutamatergic and Parvalbumin Systems of Mice Exposed to Unpredictable Chronic Stress

01 Mar 2018-Molecular Neurobiology (Mol Neurobiol)-Vol. 55, Iss: 3, pp 2591-2602
TL;DR: It is hypothesized that chronic stress-induced enhancement of glutamatergic transmission in the PFC is a crucial contributing factor to changes within the prefrontal GABAergic and, specifically, PV system, and is associated with sex-specific changes in the mRNA expression of the NR2B subunit of the NMDA receptor.
Abstract: The prefrontal cortex (PFC) is highly sensitive to the effects of stress, a known risk factor of mood disorders including anxiety and depression. Abnormalities in PFC functioning have been well described in humans displaying stress-induced depressive symptoms, and hypoactivity of the PFC is now recognized to be a key feature of the depressed brain. However, little is known about the causes and mechanisms leading to this altered prefrontal functional activity in the context of stress-related mood disorders. We previously showed that unpredictable chronic mild stress (UCMS) in mice increases prefrontal expression of parvalbumin (PV), an activity-dependent calcium-binding albumin protein expressed in a specific subtype of GABAergic neurons, highlighting a potential mechanism through which chronic stress leads to hypofunction of the PFC. In this study, we aimed to investigate the mechanisms by which chronic stress alters the prefrontal GABA system. We hypothesized that chronic stress-induced enhancement of glutamatergic transmission in the PFC is a crucial contributing factor to changes within the prefrontal GABAergic and, specifically, PV system. BALB/c male and female mice were exposed to daily handling (control) or 2 or 4 weeks of UCMS. Female mice displayed a more severe altered phenotype than males, as shown by increased anxiety- and depressive-like behaviors and deficits in PFC-dependent cognitive abilities, particularly after exposure to 2 weeks of UCMS. This behavioral phenotype was paralleled by a large increase in prefrontal PV messenger RNA (mRNA) and number of PV-expressing neurons, supporting our previous findings. We further showed that the expression of pre- and postsynaptic markers of glutamatergic transmission (VGlut1 presynaptic terminals and pERK1/2, respectively) onto PV neurons was increased by 2 weeks of UCMS in a sex-specific manner; this was associated with sex-specific changes in the mRNA expression of the NR2B subunit of the NMDA receptor. These findings provide evidence of increased glutamatergic transmission onto prefrontal PV neurons, particularly in female mice, which could potentially contribute to their increased PV expression and the extent of their behavioral impairment following UCMS. Finally, our analysis of activity of subcortical regions sending glutamatergic afferents to the PFC reveals that glutamatergic neurons from the basolateral amygdala might be specifically involved in UCMS-induced changes in prefrontal glutamatergic transmission.
Citations
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Journal ArticleDOI
TL;DR: The purpose of this review is to highlight the structural and functional diversity of AATs, their diverse physiological roles in different tissues and organs, their wide-ranging implications in human diseases and the emerging strategies and tools that will be necessary to target AATS therapeutically.

247 citations

Journal ArticleDOI
TL;DR: It is concluded that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders.
Abstract: Major depressive disorder (MDD) is a debilitating illness characterized by neuroanatomical and functional alterations in limbic structures, notably the prefrontal cortex (PFC), that can be precipitated by exposure to chronic stress. For decades, the monoaminergic deficit hypothesis of depression provided the conceptual framework to understand the pathophysiology of MDD. However, accumulating evidence suggests that MDD and chronic stress are associated with an imbalance of excitation-inhibition (E:I) within the PFC, generated by a deficit of inhibitory synaptic transmission onto principal glutamatergic neurons. MDD patients and chronically stressed animals show a reduction in GABA and GAD67 levels in the brain, decreased expression of GABAergic interneuron markers, and alterations in GABAA and GABAB receptor levels. Moreover, genetically modified animals with deletion of specific GABA receptors subunits or interneuron function show depressive-like behaviors. Here, we provide further evidence supporting the role of cortical GABAergic interneurons, mainly somatostatin- and parvalbumin-expressing cells, required for the optimal E:I balance in the PFC and discuss how the malfunction of these cells can result in depression-related behaviors. Finally, considering the relatively low efficacy of current available medications, we review new fast-acting pharmacological approaches that target the GABAergic system to treat MDD. We conclude that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders. Drugs that can establish a new E:I balance in the PFC by targeting the glutamatergic and GABAergic systems show promising as fast-acting antidepressants and represent breakthrough strategies for the treatment of depression.

199 citations

Journal ArticleDOI
TL;DR: Evidence for mPFC neurotransmission abnormalities in major depressive disorder (MDD) and their potential impact on neural circuits (mPFC/DRN) are reviewed, with results from recent preclinical studies showing that ketamine, at antidepressant-relevant doses, induces neuronal adaptations that involve the glutamate-excitatory/GABA-inhibitory balance.

97 citations

Journal ArticleDOI
TL;DR: The hypothesis that chronic stress-induced emotional dysfunction involves hypoactivity of the PFC due to increased inhibition is proposed and ideas for reconciling contradictory findings in support of the hypothesis of over-inhibition are proposed.

83 citations

Journal ArticleDOI
TL;DR: The medial prefrontal cortex (mPFC) receives information regarding stimuli and appropriately orchestrates neurophysiological, autonomic, and behavioral responses to stress, and there is mounting evidence suggesting that chronic stress may precipitate E/I imbalance as mentioned in this paper.

63 citations

References
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Journal ArticleDOI
TL;DR: Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups.
Abstract: Context Little is known about lifetime prevalence or age of onset of DSM-IV disorders. Objective To estimate lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the recently completed National Comorbidity Survey Replication. Design and Setting Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview. Participants Nine thousand two hundred eighty-two English-speaking respondents aged 18 years and older. Main Outcome Measures Lifetime DSM-IV anxiety, mood, impulse-control, and substance use disorders. Results Lifetime prevalence estimates are as follows: anxiety disorders, 28.8%; mood disorders, 20.8%; impulse-control disorders, 24.8%; substance use disorders, 14.6%; any disorder, 46.4%. Median age of onset is much earlier for anxiety (11 years) and impulse-control (11 years) disorders than for substance use (20 years) and mood (30 years) disorders. Half of all lifetime cases start by age 14 years and three fourths by age 24 years. Later onsets are mostly of comorbid conditions, with estimated lifetime risk of any disorder at age 75 years (50.8%) only slightly higher than observed lifetime prevalence (46.4%). Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups. Conclusions About half of Americans will meet the criteria for a DSM-IV disorder sometime in their life, with first onset usually in childhood or adolescence. Interventions aimed at prevention or early treatment need to focus on youth.

17,213 citations

Book
31 Jul 2001
TL;DR: The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use and includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material.
Abstract: "The Mouse Brain in Stereotaxic Coordinates" is the most widely used and cited atlas of the mouse brain in print. It provides researchers and students with both accurate stereotaxic coordinates for laboratory use, and detailed delineations and indexing of structures for reference. The accompanying DVD provides drawings of brains structures that can be used as templates for making figures for publication. The 3rd edition is both a major revision and an expansion of previous editions. Delineations and photographs in the horizontal plane of section now complement the coronal and sagittal series, and all the tissue sections are now shown in high resolution digital color photography. The photographs of the sections and the intermediate sections are also provided on the accompanying DVD in high-resolution JP 2000 format. The delineations of structures have been revised, and naming conventions made consistent with Paxinos and Watson's "Rat Brain in Stereotaxic Coordinates, 6th Edition". The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use. This edition is in full color throughout. It includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material. Coronal and sagittal diagrams are completely reworked and updated. Rhombomeric borders are included in sagittal figures, for the first time in mammals. Microscopic plates are scanned with a new method in much higher quality.

15,681 citations

Journal ArticleDOI
TL;DR: Using positron emission tomography, cerebral glucose metabolism in drug-free, age- and sex-matched, right-handed patients with unipolar depression, bipolar depression, obsessive-compulsive disorder (OCD) with secondary depression, OCD without major depression, and normal controls is studied.
Abstract: • Using positron emission tomography, we studied cerebral glucose metabolism in drug-free, age- and sex-matched, righthanded patients with unipolar depression (n =10), bipolar depression (n =10), obsessive-compulsive disorder (OCD) with secondary depression (n =10), OCD without major depression (n =14), and normal controls (n =12). Depressed patients were matched for depression on the Hamilton Depression Rating Scale, and subjects with OCD without depression and OCD with depression had similar levels of OCD pathology. We also studied six non—sex-matched patients with mania. Mean ( ± SD) glucose metabolic rates for the left dorsal anterolateral prefrontal cortex, divided by the rate for the ipsilateral hemisphere as a whole (ALPFC/hem), were similar in the primary depressions (unipolar depression = 1.05 ±0.05; bipolar depression =1.04 ± 0.05), and were significantly lower than those in normal controls (1.12 ± 0.06) or OCD without depression (1.15 ± 0.05). Results for the right hemisphere were similar. Values in subjects with OCD with depression (1.10 0.05) were also significantly lower than in subjects with OCD without depression, and values in subjects with bipolar depression were lower than those in manic subjects (1.12 ± on this measure in the left hemisphere, although results were not significant in the right hemisphere. There was a significant correlation between the HAM-D score and the left ALPFC/hem. With medication for depression (n =12), the left ALPFC/hem increased significantly and the percentage change in the Hamilton scale score correlated with the percentage change in the left ALPFC/hem. These data support other findings that major depression is associated with a left ALPFC abnormality.

1,288 citations

Journal ArticleDOI
TL;DR: When assessing the behaviour of mice, it is necessary to increase the range of behavioural paradigms used, including animal models of "state" and "trait" anxiety.

870 citations

Journal ArticleDOI
TL;DR: In addition to the delineation of interactions between neurotransmitters, the spontaneous alternation test is sensitive to the consequences of normal and pathological aging.

702 citations