Altered Excitation-inhibition Balance in Depression and Stress: Contributing Pathology and Treatment Target

Lifetime exposure to severe or lasting stressors is a shared risk factor across psychiatric illnesses that together account for one-third of global years lost due to disability, including major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD). Evidence from human and animal studies demonstrates alterations in cellular and molecular components of excitation-inhibition balance (EIB) as central to these illnesses. These include deficits among excitatory glutamatergic neurons, inhibitory GABAergic interneurons, and glial cells. Concurrently, first-line antidepressant drugs (ADs) achieve insufficient response, low remission, and high relapse rates, in part because they do not directly target primary pathological alterations to EIB components. Although recent advancements have been made with rapid-acting ADs targeting excitatory alterations, several pathological targets among EIB components remain unexplored. This thesis investigated how deficits in cellular and regional mediators of EIB, as informed by human pathological findings, contribute to preclinical behaviors reflecting symptoms of chronic stress-related disorders. Using transgenic mice with brain-wide low somatostatin-positive GABAergic interneuron (“SST+ cell”) function, we first identified that inhibitory SST+ cells regulate depressive-, anxiety-, and anhedonia-like behaviors, plus memory impairment, supporting evidence that primary SST+ cell deficits in humans contribute to MDD symptoms (Study 1). In chronic stress-exposed mice, we next identified that stress-related behavioral deficits emerge partly through altered EIB, specifically, enhanced functional activation of the anterior cingulate cortex and ventral hippocampus (Study 2). We then evaluated the therapeutic potential of novel AD strategies targeting excitatory homeostasis or inhibitory components of EIB. Prophylactic administration of riluzole, a drug that regulates excitatory glutamate homeostasis, enhanced resilience in chronic stress-exposed mice (Study 3). In transgenic mice with SST+ cells silenced, potentiation of α5-GABA-A receptors (that partially mediate inhibitory SST+ cell functions) revealed antidepressant potential, demonstrating a proof-of-concept for emerging therapeutic mechanisms bypassing SST+ cell pathological changes (Study 1). These studies contribute evidence linking disrupted EIB to behavioral deficits related to symptoms of psychiatric illnesses and support antidepressant mechanisms targeting components of altered EIB. The insights from this work have potential to advance precision diagnosis and treatment of MDD and other neuropsychiatric disorders linked to chronic stress.Ph.D