Regulation of Mood by Interneuron Dopamine D1 Receptors

Major Depressive Disorder (MDD) produces the greatest decrement in health when compared to other chronic diseases. Depression has genetic, epigenetic, and environmental contributions; that include the involvement of chronic and acute stressors as an important environmental contributor in causing MDD. A number of patients do not respond to treatment to newly developed medications and therefore resulting in a high failure rate, additionally, a significant proportion of MDD patients are “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. Dopaminergic systems, in the past decades, have become an important substrate to explore in people suffering from anxiety and depressive disorders since they have been shown to 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 we delete the Drd1 gene 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 PFC and provides protection from acute and chronic stress. My Ph.D. thesis is focused on addressing the questions below:

1) Any neuroendocrine and neurobehavioral responses to stress following the developmental and cell-type specific deletion of D1 receptors in cerebral cortical interneurons derived from the Nkx2.1 lineage (MGE-Drd1-cKO)?

2) Any Structural and cellular correlates of reduced depression-related responses in the prefrontal cortex (PFC) of MGE-Drd1-cKO mice?

3) Does loss of Drd1 in PV+ neurons phenocopy stress-resilient phenotypes?

The need for more effective therapies for the treatment of depression remains pressing; a significant proportion of major depressive disorder patients remain resistant to currently available treatments. Our goal in this proposal is to address this need by identifying a new therapeutic target that will inevitably lead to new innovative strategies for developing more efficient therapeutics for this disease. Some studies suggest that cell-specific neuropharmacology strategies with location-biased ligands could be a possibility.

The selective deletion of D1 receptors from MGE-derived GABAergic neurons provides a powerful animal model with the translational potential to examine the roles of this subset of cortical interneuron in both neuropathological processes and in promoting adaptive mechanisms contributing to behavioral and cognitive resilience. Therefore, blocking D1 receptors expressed on cortical interneurons may represent a new and exciting mechanism to treat MDD.