Section Major depressive disorder (MDD) is a leading cause of total disability with inadequate treatment options and unresolved underlying biology. However, diverse environmental stressors are widely recognized as major culprits in the etiology of MDD Mounting evidence suggests that environmental stressors and other causes of MDD converge on a reduced ratio of GABAergic and glutamatergic synaptic transmission (E/I ratio), while antidepressant therapies appear to act over time to augment GABAergic transmission and reverse such imbalances. In support of such mechanisms we have generated mice with enhanced GABAergic transmission by disinhibiting somatostatin positive GABAergic interneurons through conditional deletion of the gamma2 subunit of GABA(A) receptors selectively from these interneurons. Indeed, SSTCre:gamma2(f/f) mice exhibit a robust antidepressant- and anxiolytic-like phenotype, along with reduced phosphorylation of the eukaryotic elongation factor 2 (eEF2), which serves as a recognized biochemical endpoint of ketamine and other rapid-acting antidepressants. Here we propose to extend this line of experimentation and assess whether SSTCre:gamma2(f/f) mice are also resilient to the detrimental effects of chronic stress. Male and female SSTCre:gamma2(f/f) will be subjected to a 6-week uncontrolled chronic mild stress (UCMs) paradigm or stress-free control conditions and then examined for resilience to stress with respect to changes in emotional behavior (Specific Aim 1), biochemical markers indicative of antidepressant drug action (Specific Aim2), cellular changes indicative of detrimental effects of stress (Specific Aim 3) and synaptic/functional changes that are normally observed after stress (Specific Aim 4).
Section Stress based neuropsychiatric disorders are leading causes of total disability with inadequate treatment options and unclear underlying biology. Currently available drug therapies are ineffective in almost half of patients and their mechanism remains poorly understood. In a search for novel approaches for the treatment of stress based neuropsychiatric disorders we here make use of a newly established mouse model of an antidepressant brain state to elucidate molecular, cellular and neurophysiological substrates that confer resilience to stress.
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