Cortical GABAergic mechanisms underlying rapid and sustained antidepressant responses

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PROJECT SUMMARY Currently available antidepressants have serious limitations for treating major depressive disorder (MDD), including low response rates, a significant number of treatment resistant patients, and a time-lag before there is a therapeutic response. Notably, ketamine, an NMDA receptor blocker, has demonstrated promise in clinical trials because of its rapid and sustained antidepressant effects. Although its mechanisms of action are still to be elucidated, our previous studies suggest that ketamine first inhibits cortical GABA interneurons, leading to disinhibition of excitatory pyramidal neurons, and subsequently, a glutamate burst, which results in synaptic plasticity and fast antidepressant responses. However, the effects of ketamine seem to be more complex than a simple enhancement of glutamatergic function, since MDD subjects and stressed animals show robust GABAergic deficits in cortical brain areas, which can be reversed by ketamine treatment. In addition, drugs that target the GABA system via α5-containing GABAA receptors (α5-GABAAR) have also been shown to produce fast and sustained behavioral effects in rodents. Therefore, the goal of this project is to extend our previous work and investigate how excitatory and inhibitory neuronal mechanisms interact to promote GABA-mediated plasticity that culminates in ketamine-induced behavioral responses, and explore additional GABAergic compounds relevant to MDD treatment, including α5-GABAAR modulators. We will test the novel hypothesis that, in addition to glutamate-induced plasticity, increased GABA function in the medial prefrontal cortex (mPFC) is critical for the synaptic and behavioral effects of fast-acting antidepressants. This hypothesis will be investigated by integrating multiple levels of analysis, including pharmacological, molecular, genetic, behavioral and electrophysiological approaches. We will address the following aims: 1) To characterize neural coding and the underlying GABAergic mechanisms in the mPFC involved in the actions of ketamine relevant to its antidepressant efficacy, 2) To investigate electrophysiological and synaptic mechanisms involved in teh behavioral actions of α5-GABAAR NAMs and PAMs and, 3) To investigate the role of α5-GABAAR in different neuronal subpopulations in mediating electrophysiological responses in the mPFC and associated behavioral outcomes. In addition to significant scientific advances in understanding the pathophysiology of depression and identifying potential novel antidepressant agents, this K99 proposal will provide training and mentorship for Dr. Fogaça that will increase her technical and academic skills, preparing her to become an independent academic scientist with her own research laboratory and program. Under the mentorship of Dr. Marina Picciotto, co-mentorship of Dr. George Dragoi and the guidance of an advisory committee (Drs. Taylor and DiLeone), Dr. Fogaça will acquire extensive training in electrophysiology in awake, behaving mice, and additional career development training, which in combination with her array of technical skills, will equip her to transition to the independent phase as an Assistant Professor, and to apply for R01 funding at the end of the R00 phase.