Synaptic Blues: Corticosteroids and AMPA Receptor Function in Depression and Antidepressant Action

Abstract

The pathophysiology underlying depression remains elusive, despite decades of research. Depression is most commonly treated, often unsatisfactorily, by manipulating synaptic serotonergic tone, yet the key substrates that mediate antidepressant efficacy are unknown. Chronic stress-based models recapitulate a depressive-like phenotype, but it is unclear how stress leads to specific neurobiological changes to induce a depressive-like neurobehavioral state. I used electrophysiology, molecular biology, and behavioral assays in rats and mice to address the inextricably linked questions "how do we become depressed?" and "how do antidepressants work?" I first contributed to the discovery that 5HT1BR-mediated increase in AMPA receptor function, via CaMKII phosphorylation of the S831 residue of GluA1, is a necessary action of serotonergic antidepressants, and contributed to the identification of hippocampal temporoammonic(TA)-CA1 synapses as a key site of dysregulation and serotonergic action in depression. Using the chronic unpredictable stress (CUS) model, I demonstrated that the TA-CA1 deficits caused by chronic stress are mediated by decreased synaptic GluA1 expression and AMPA receptor strength specific to distal apical dendrites. Decreased AMPA:NMDA stoichiometry at TA-CA1 synapses correlated with decreased sucrose preference scores, a model of anhedonia. In asking how CUS causes these synaptic and behavioral deficits, I found that chronic elevations in corticosterone(CORT) are both sufficient and necessary by administering exogenous CORT in lieu of CUS and by administering metyrapone (a corticosteroid synthesis inhibitor) during CUS, respectively. My results support a hypothesis that depression results from synaptic deficits at key excitatory synapses in cortico-mesolimbic circuitry, that these deficits are induced by chronic stress via corticosterone, and that antidepressant efficacy is mediated by reversing these synaptic deficits. This hypothesis suggests a novel antidepressant strategy by which other compounds or interventions can rapidly restore affective state by reversing chronic-stress- and corticosterone-induced deficits in excitatory synapses. Consistent with this hypothesis, I also participated in a study showing that negative modulators of GABAA receptor function act as rapid antidepressants and restore AMPAR-mediated excitatory strength at TA-CA1 synapses.