Dysregulation of prefrontal cortex (PFC) dopaminergic signaling is associated with multiple neuropsychiatric diseases, including depression, bipolar disorder, and schizophrenia. Current antipsychotics have high affinity for Gi/o-coupled D2 and D3 receptors (D2R, D3R). While there has been considerable focus on the role of prefrontal D2Rs in neuropsychiatric disease, there is emerging evidence that the D3R is also critically important. However, we know very little about the cellular distribution and function of D3Rs in prefrontal circuits, or how antipsychotics regulate their function. The goal of this proposal is to determine the neuronal distribution and function of D3R in prefrontal cortex, the cellular mechanisms by which D3R regulates neuronal excitability, and the mechanisms by which antipsychotics regulate their function. We will use a combination of electrophysiology, 2-photon imaging, and molecular biology in native and heterologous systems to examine D3R signaling mechanisms, with particular focus on the potential role of arrestin-mediated signaling. Results of this study will provide insight into how PFC networks function normally and abnormally in psychiatric disease.
This work focuses on the circuits that express D3 dopamine receptors in prefrontal cortex, and the function and signaling mechanisms of D3 receptors in these circuits. This is important because D3 receptors are a major target of currently prescribed antipsychotics, but how antipsychotics regulate D3 receptor function in cortex is unclear. This work may shed light on the cellular mechanisms that antipsychotics engage to treat schizophrenia, bipolar disorder, and obsessive compulsive disorder, and may direct future drug development to improve side effect profiles.
|Clarkson, Rebecca L; Liptak, Alayna T; Gee, Steven M et al. (2017) D3 Receptors Regulate Excitability in a Unique Class of Prefrontal Pyramidal Cells. J Neurosci 37:5846-5860|
|Yang, Sungchil; Ben-Shalom, Roy; Ahn, Misol et al. (2016) ?-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment. Cell Rep 16:1518-1526|