Effects of pre‐ and postnatal corticosterone exposure on the rat hippocampal GABA system

Abstract

Several lines of evidence have implicated prenatal stress and the hippocampal GABA system in the pathophysiology of schizophrenia, and prenatal stress is believed to increase the risk for schizophrenia through alterations of this neurotransmitter. To explore this hypothesis, we treated male rats pre- and/or postnatally (P48 and P60) with either corticosterone (CORT) or vehicle to establish three study groups: VVV, receiving vehicle at all three time points; VCC, receiving vehicle prenatally and CORT at both postnatal timepoints; and CCC, receiving CORT at all three timepoints. Animals were sacrificed at either 24 h or 5 days after final injection and examined for mRNA levels of GAD65, GAD67, and the GABA(A) receptor subunits alpha2 and gamma2. At 24 h, GAD65 mRNA was decreased in CA1, CA2, CA4, and dentate gyrus (DG) of VCC rats; this effect was either decreased or reversed in CCC-treated animals. No effect was detected in GAD67 mRNA at 24 h. At 5 days, CORT treatment increased GAD67 mRNA levels in CA1, CA3, and DG. Prenatal treatment with CORT was associated with increased responsiveness only in CA3 and DG. For the GABAA receptor, alpha2 subunit mRNA did not show any change in response to CORT treatment, while that for the gamma2 subunit was decreased in CA2 of both VCC- and CCC-treated animals. Consistent with gamma2 subunit mRNA decreases, benzodiazepine (BZ) receptor binding activity was decreased in CA2 with CORT treatment. Prenatal CORT exposure neither increased nor decreased this effect. These results demonstrate that CORT administration is associated with a complex regulation of mRNA expression for pre- and postnatal aspects of the hippocampal GABA system. Under these conditions, prenatal exposure to CORT may sensitize some of these effects, but does not fundamentally alter the nature of this response.

Increased density of GAD65/67 immunoreactive neurons in the posterior subiculum and parahippocampal gyrus in treated patients with chronic schizophrenia

“…However, we could not show an association between GAD cell density and disease duration in male patients with schizophrenia. One possible explanation could be that estradiol and progesterone increase the content of GAD, as it has been shown in animal studies (Guerra-Araiza et al colleagues investigated the effect of chronic cortisol exposure on the expression of GAD65/67 mRNA and protein in rat and primate hippocampus (Stone et al 2001;McMillan et al 2004). Using an antibody that detected both isoforms of GAD protein, McMillan et al revealed a signifi cant up-regulation of expression in response to cortisol in macaque ' s hippocampus.…”

Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders

“…Rat offspring of “stressed” mothers, through restraint or external corticosterone administration, have fewer post-synaptic benzodiazepine binding sites and GABA A receptor subunits in the hippocampus 47, 48 and amygdala. 49, 50 The cause of these post-synaptic modifications is unclear—it may be a direct consequence of prenatal stress on receptors or a compensation due to changes in ligand activity.…”

“…Studies of how the hippocampus changes in response to acute stress demonstrate that the direction of stress-reactive expression of GAD enzymes is not fundamentally changed. 48 Typically, GAD65 decreases after a single exposure to stress hormone and increases after two exposures. Prenatal stress causes only a small increase in this reactivity 48 in mRNA expression per cell, not overall expression in the region.…”

Postnatal steroid treatment and brain development

“…These findings are consistent with another study showing complex alterations in the levels of GAD65 and GAD67 gene transcription in the hippocampus. 57 In rats, repeated dexamethasone injections during the second week of life also enhanced the maturation of postnatal cholinergic neurones by increasing nerve growth factor concentrations. 58 Thus, alterations in neuronal maturation may account in part for the adverse neurodevelopmental effects of postnatal dexamethasone treatment in premature infants.…”