Neuroadaptations of presynaptic and postsynaptic GABAB receptor function in the paraventricular nucleus in response to chronic unpredictable stress

Abstract

Background and purpose: Chronic stress impairs GABA_A (GABA type A) receptor-mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABA_B receptor function is also altered. We hypothesize that chronic stress alters GABA_B receptor function in PVN corticotrophin-releasing hormone (CRH) neurons to control hypothalamus-pituitary-adrenal axis activity.

Experimental approach: Whole-cell patch clamp recordings were made of PVN-CRH neurons expressing eGFP driven by CRH promoter in brain slices from unstressed rats and rats exposed to chronic unpredictable mild stress (CUMS).

Key results: CUMS elevated the basal circulating corticosterone levels and increased the basal firing activity of PVN-CRH neurons. Microinjection of GABA_B receptor agonist baclofen into the PVN suppressed the increased corticosterone levels in CUMS rats compared with unstressed rats. CUMS blunted the baclofen-induced inhibition on PVN-CRH neurons and outward currents in these neurons. Furthermore, CUMS reduced expression of GABA_B1 (GABA_B R1) protein in the PVN. Blocking NMDA receptors with AP5 restored the reduced baclofen-induced currents in CUMS rats but had no effect on GABA_B1 expression. Furthermore, CUMS treatment augmented the baclofen-induced decrease in the frequency of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitor postsynaptic currents in PVN-CRH neurons. The GABA_B receptor antagonist CGP55845 increased the firing activity of PVN-CRH neurons only in CUMS-treated rats and not in unstressed rats.

Conclusions and implications: These findings suggest that chronic stress impairs postsynaptic GABA_B receptor function but augments presynaptic GABA_B receptor function in controlling glutamatergic and GABAergic synaptic inputs in PVN-CRH neurons.