Chronic stress has different immediate and delayed effects on hippocampal calretinin- and somatostatin-positive cells

Past studies find that chronic stress alters inhibitory, GABAergic circuitry of neurons in distinct hippocampal subregions. Less clear is whether these effects persist weeks after chronic stress ends, and whether these effects involve changes in the total number of hippocampal GABAergic neurons or modulates the function of specific GABAergic subtypes. A transgenic mouse line (VGAT:Cre Ai9) containing an indelible marker for GABAergic neurons (tdTomato) throughout the brain was used to determine whether chronic stress alters total GABAergic neuronal number or the expression of two key GABAergic cell subtypes, calretinin expressing (CR+) and somatostatin expressing (SOM+) neurons, and whether these changes endure weeks later. Male and female mice were chronically stressed in wire mesh restrainers for 6h/d/21d (Str) or not (Con), and then allowed a 3 week rest period (Str-Rest) and compared to those without a rest period (Str-NoRest). Epifluorescent microscope images of immunohistochemistry-processed brains were quantified to estimate the total number of fluorescently-labeled hippocampal GABAergic neurons and the proportion that were CR+ or SOM+. Neither chronic stress nor sex altered the total number of GABAergic cells. In contrast, chronic stress reduced the expression of CR+ in the CA3 region of the hippocampus in both males and females, with robust reductions in the DG region of males, but not females, and these changes reversed following a rest period. Chronic stress also reduced the proportion of hippocampal SOM+ neurons and this reduction persisted even with a rest period. These results show chronic stress dynamically reduced CR expression without changing total inhibitory neuronal number and point to CR as a potential new lead to understand mechanisms by which chronic stress alters hippocampal function.

Automated summary

Chronic stress affects the inhibitory GABA circuitry in distinct hippocampal subregions without altering the total number of GABAergic neurons. It reduces the expression of CR+ in the CA3 region and DG region of the hippocampus, especially in males, but these changes reverse after a rest period. Chronic stress also decreases the proportion of hippocampal SOM+ neurons, and this reduction persists even with a rest period.