Glucocorticoids Modulate Expression of Perineuronal Net Component Genes and Parvalbumin During Development of Mouse...

Severe prenatal maternal stress is a risk factor for schizophrenia in offspring. Since parvalbumin-containing GABAergic interneuron function in the cortex and hippocampus is compromised in schizophrenia, and perineuronal nets (PNNs) facilitate the functioning of these cells, we tested the hypothesis that glucocorticoids, as stress mediators that can access the foetal compartment, might influence the expression of PNN component genes. In cultured mouse cortical neurons, we detected effects of hydrocortisone on many PNN component genes, via diverse mechanisms. A rapid (< 4 h), glucocorticoid receptor (GR)-mediated suppression of neurocan and hyaluronan synthase (Has) 1 and 3 mRNAs was observed at 7 days in vitro (DIV), whereas at 14 DIV, brevican and versican expression was reduced by hydrocortisone without GR involvement, while GR inhibition elevated Has1 and Has2 mRNA levels and suppressed aggrecan mRNA levels. Tenascin R expression was rapidly suppressed by hydrocortisone at 7 DIV but not at 14. At 21 DIV, PNN component gene expression had become insensitive to hydrocortisone, although parvalbumin expression was reduced after 24 h but not 4 h exposure. Additionally, effects on protein levels were observed that were sometimes consistent with the mRNA changes (e.g. Has3, Gad1) and sometimes unrelated to them (e.g. elevated TnR levels at 7 DIV after glucocorticoid receptor antagonism). We found that hydrocortisone could directly inhibit proteasome activity. As expected from these results, the overall structure of the PNN was compromised by hydrocortisone exposure, with the length of the proximal dendrite covered by PNN being reduced. Overall, the data demonstrate a complex and profound, but developmental stage-dependent, regulation of PNN component gene expression by glucocorticoids. This may contribute to the action of severe prenatal or perinatal stress to increase schizophrenia risk.