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

BACKGROUND AND PURPOSE

Chronic stress impairs GABA (GABA type A) receptor-mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABA receptor function is also altered. We hypothesize that chronic stress alters GABA 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 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 (GABA 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 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 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 receptor function but augments presynaptic GABA receptor function in controlling glutamatergic and GABAergic synaptic inputs in PVN-CRH neurons.