Roles of Hippocampal Alpha 6 GABAA Receptors in ClomipramineAlleviating Chronic Repeated Restraint Stress-Induced DepressiveBehaviors in Rats

Introduction: GABAergic deficits are involved in depressive disorders; the roles of hippocampal GABAA receptors in the pathogenesis and pharmacotherapy of depression have not been fully studied. The hippocampal alpha 6 GABAA receptors (α6, Gabra6) have a critical role in the pathophysiology of major depressive disorder. The present study determined the roles of α6 subunits in the pathogenesis and antidepressant treatment of depression in a rat model of major depression induced by Chronic Repeated Restraint (CRR). Materials and Methods: Male Sprague-Dawley rats were restrained daily in an air-accessible Plexiglas cylindrical restrainer. The tricyclic antidepressant clomipramine was provided to rats daily by drinking (50 mg/kg) after restraint stress. The novelty suppressed feeding tests, open field tests, and sucrose preference tests were performed to evaluate depressive behaviors in rats. QPCR was performed to measure Gabra6 mRNA levels in rat hippocampus, and immunohistochemistry was performed to detect α6 protein localization in the hippocampus. The patch-clamp technique was used to test the electrophysiological characteristics of evoked inhibitory postsynaptic currents (eIPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) in hippocampal CA1 pyramidal neurons. Results: We observed that CRR stress decreased sucrose preference, travel distance, and center time in the open field test, and increased latency to feed in the novelty-suppressed feeding test. α6 subunits were mainly expressed on interneurons in CA1 of the hippocampus. CRR stress down-regulated α6 subunits of the GABAA receptor in the hippocampus. Patch-clamp studies revealed that CRR stress decreased the amplitude of eIPSCs while increasing the frequencies and amplitudes of sIPSCs in CA1 pyramidal neurons, indicating that inhibitory synaptic transmission in the hippocampus was altered by CRR stress. Chronic administration of clomipramine ameliorated depressive behaviors, restored the normal expression of hippocampal α6 subunits, and decreased sIPSC frequencies of pyramidal neurons in rats subjected to CRR stress. Discussion: These results suggest that clomipramine-induced upregulation of α6 subunits attenuated abnormal inhibitory synaptic transmission in the hippocampus, which might contribute to its antidepressant actions in relieving depressive behaviors induced by CRR stress. Conclusions: The roles of α6 subunits in the pathogenesis and antidepressant treatment of depression may provide novel therapeutic avenues for the development of antidepressants.