Cortical glutamatergic and GABAergic dysfunction in stress-related disorders and reversal by novel treatments

Abstract:

Major Depressive Disorder (MDD) is a recurring neuropsychiatric illness that affects nearly 1 in 5 individuals during their lifetime and is a leading cause of disability worldwide. While the mechanisms underlying the pathophysiology of MDD remain to be fully elucidated, growing evidence highlights the impact of chronic stress exposure in inducing neuronal atrophy in glutamatergic neurons and reducing the function of GABAergic interneurons, notably somatostatin and parvalbumin subtypes, within the medial prefrontal cortex (mPFC). These changes disrupt the optimal balance between cortical excitation and inhibition (E:I), compromising the signal transfer to target regions and leading to maladaptive states that can result in stress-related conditions. Despite MDD's high prevalence, traditional treatments exhibit suboptimal effectiveness. A notable breakthrough in drug intervention comes from the discovery that low doses of ketamine, an NMDA receptor (NMDA-R) blocker, induce rapid and sustained antidepressant effects, although with significant side effects like psychotomimetic actions, limiting its therapeutic use. In parallel with animal model studies of stress, investigating the mechanisms of rapid antidepressants, including ketamine and scopolamine (a non-selective muscarinic acetylcholine receptor antagonist), holds promise in unraveling complex circuit changes in MDD's pathophysiology. This talk offers an overview of combined approaches, including molecular neuropharmacology, genetic studies, and circuit-level investigations, to explore how the crosstalk between specific neuronal subpopulations in the mPFC modulates glutamatergic and GABAergic function, leading to phenotypes relevant to stress disorders and to the actions of fast antidepressants. Moreover, the talk provides new insights into emerging classes of drugs that directly or indirectly target the glutamatergic and/or GABAergic systems as rapid antidepressants, representing novel approaches for MDD treatment.

About the Speaker:

Dr. Fogaça is a recently appointed Assistant Professor in the Department of Pharmacology and Physiology at the University of Rochester (URMC). Before starting her current position, she served as a postdoctoral fellow in the Department of Psychiatry at Yale University, initially under the guidance of the late Prof. Ronald Duman and subsequently in Prof. Marina Picciotto’s lab. In her studies, Dr. Fogaça investigated molecular, cellular, and synaptic mechanisms underlying the rapid and sustained actions of fast antidepressants, notably ketamine and its metabolites, as well as scopolamine. Dr. Fogaça earned her Master’s and PhD in Pharmacology at the University of Sao Paulo (FMRP-USP, Brazil), focusing on unraveling the molecular mechanisms of action of cannabinoid compounds across various brain systems implicated in stress-related disorders. She has authored approximately 40 peer-reviewed papers and book chapters in internationally recognized journals. In addition, she has obtained multiple awards and highly competitive grants to fund her work, including the NARSAD Young Investigator Award and the K99/R00 NIH Pathway to Independence Award. Currently, research in the Fogaça lab focuses on understanding the molecular basis of behaviors relevant to stress and the actions of fast antidepressant drugs, aiming to identify specific circuits, neuronal subpopulations, and synaptic mechanisms involved in these responses. Towards this goal, her lab combines neuropharmacology, genetic approaches, and circuit-level studies to explore new pharmacological strategies for treating major depressive disorder, including compounds that target the glutamatergic and/or GABAergic systems in the brain.

Contact

Bernhard Luscher
bxl25@psu.edu