Major Depressive Disorder (MDD) produces the greatest decrement in health when compared to other chronic diseases. Depression has genetic, epigenetic, and environmental contributions, including chronic and acute stressors as an important environmental factor in causing MDD. A substantial proportion of patients do not respond to newly developed medications, resulting in a high treatment-failure rate; a significant proportion of MDD patients are considered "treatment-resistant." Many existing drug treatments for depression focus on the neurotransmitter serotonin; however, previous studies have also found important roles for the neurotransmitter dopamine (DA) in regulating mood and affect. Over the past decades, dopaminergic systems have become an important substrate to explore in people suffering from anxiety and depressive disorders, since they contribute to the underlying pathophysiological changes in mood and cognitive disorders.
My laboratory recently discovered that D1 receptors expressed on a specific subpopulation of cerebral cortical interneurons regulate mood-related behaviors and brain circuits. We created a model system in which the Drd1 gene is deleted from medial ganglionic eminence-derived (MGE) GABAergic neurons (future GABAergic cortical interneurons); behavioral assessment of those mice showed strong antidepressant-like phenotypes. My project assesses stress responses in these mice and tests the hypothesis that cell-type-specific inactivation of D1 receptors in cortical interneurons derived from the Nkx2.1 lineage (MGE-Drd1-cKO mice) alters their cellular and molecular circuitry in the prefrontal cortex (PFC) and provides protection from acute and chronic stress. My Ph.D. thesis addresses three questions:
- Are there neuroendocrine and neurobehavioral responses to stress following developmental, cell-type-specific deletion of D1 receptors in cerebral cortical interneurons derived from the Nkx2.1 lineage (MGE-Drd1-cKO)?
- What structural and cellular correlates underlie the reduced depression-related responses in the prefrontal cortex of MGE-Drd1-cKO mice?
- Does loss of Drd1 in PV+ neurons phenocopy stress-resilient phenotypes?
The need for more effective therapies for depression remains pressing; a significant proportion of major depressive disorder patients remain resistant to currently available treatments. Our goal is to address this need by identifying a new therapeutic target that can lead to more effective treatments for this disease. Some evidence suggests that cell-specific neuropharmacology strategies using location-biased ligands could be a viable path forward.
The selective deletion of D1 receptors from MGE-derived GABAergic neurons provides a powerful animal model with translational potential for examining the roles of this subset of cortical interneurons in both neuropathological processes and adaptive mechanisms that contribute to behavioral and cognitive resilience. Blocking D1 receptors expressed on cortical interneurons may therefore represent a new and promising mechanism for treating MDD — particularly for the subset of patients who don't respond to existing antidepressants.