Chronic stress reduces the number of GABAergic interneurons in the adult rat hippocampus, dorsal-ventral and region-specific differences

Abstract

Major depressive disorder is a common and complex mental disorder with unknown etiology. GABAergic dysfunction is likely to contribute to the pathophysiology since disrupted GABAergic systems are well documented in depressed patients. Here we studied structural changes in the hippocampal GABAergic network using the chronic mild stress (CMS) model, as one of the best validated animal models for depression. Rats were subjected to 9 weeks of daily stress and behaviorally characterized using the sucrose consumption test into anhedonic and resilient animals based on their response to stress. Different subtypes of GABAergic interneurons were visualized by immunohistochemistry using antibodies for parvalbumin (PV), calretinin (CR), calbindin (CB), cholecystokinin (CCK), somatostatin (SOM), and neuropeptide Y (NPY). We used an unbiased quantification method to systematically count labeled cells in different subareas of the dorsal and ventral hippocampus. Chronic stress reduced the number of specific interneurons in distinct hippocampal subregions significantly. PV+ and CR+ neurons were reduced in all dorsal subareas, whereas in the ventral part only the CA1 was affected. Stress had the most pronounced effect on the NPY+ and SOM+ cells and reduced their number in almost all dorsal and ventral subareas. Stress had no effect on the CCK+ and CB+ interneurons. In most cases the effect of stress was irrespective to the behavioral phenotype. However, in a few specific areas the number of SOM+, NPY+, and CR+ neurons were significantly reduced in anhedonic animals compared to the resilient group. Overall, these data clearly demonstrate that chronic stress affects the structural integrity of specific GABAergic neuronal subpopulations and this should also affect the functioning of these hippocampal GABAergic networks.

Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms: Restorative Effect of the Antipsychotic Lurasidone

“…Similar results were obtained with other stress paradigms in rats, such as chronic immobilization (Hu et al, 2010) and social isolation (Filipović et al, 2013). Interestingly, in our experimental setting, the D-HIP appears to be more vulnerable to the impact of CMS, an effect that is in line with the results of Czeh and co-workers (Czéh et al, 2015). Considering that functional alterations of this hippocampal subregion have a major role in cognitive dysfunctions, we hypothesize that reduced PVB expression may contribute to the impaired cognitive function we have recently shown in rats exposed to the CMS paradigm (Calabrese et al, 2017).…”

“…In more detail, GABAergic interneurons synchronize the firing of principal cells controlling the plasticity of excitatory synaptic inputs through dendritic inhibition, while they inhibit the output with perisomatic inhibition (Freund, 2003). Among the diverse subtypes of GABAergic interneurons populating the hippocampal formation, parvalbumin (PVB), somatostatin (SST), calbindin (CALB), and neuropeptide-Y (NPY) positive cells represent the most sensitive to stress exposure (Filipovic et al 2013; Czeh et al 2015). Specifically, the highly energized, fast-spiking, PVB positive (PVB+) interneurons play a pivotal role in the processing of complex information.…”

Longitudinal in vivo Diffusion Tensor Imaging Detects Differential Microstructural Alterations in the Hippocampus of Chronic Social Defeat Stress-Susceptible and Resilient Mice

“…However, after stress, a greater microstructural alteration was demonstrated in the dHi than in the vHi, especially in the resilient group. Consistent with our findings, an analysis of the change in the number of hippocampal interneurons of specific subtypes after CMS revealed a more pronounced effect on the dHi than vHi (Czeh et al, 2015). Moreover, CUS selectively decreased cell survival in the vHi, while it induced adaptive neuroplasticity primarily in the dHi, which was closely related to the following behavioral responses, such as avoidance or amelioration of the stressor (Hawley and Leasure, 2012).…”

Stress and Loss of Adult Neurogenesis Differentially Reduce Hippocampal Volume

“…If neither change in neurogenesis nor in dendritic arborization can explain the observed volume loss, it is still unclear what cellular changes are responsible. Several other known effects of stress, including decreased numbers of inhibitory interneurons throughout the hippocampus (68), decreased numbers of glia in the neuropil (69), and decreased hippocampal microvasculature (70) are potential factors. Glial cells, particularly astrocytes, are reduced in number and size in both human depression and animal models of chronic stress (71–73), suggesting a potential contribution to volume change.…”