Mechanisms of Dopamine D3 Receptor Mediated Antipsychotic Action in the Hippocampus

Schizophrenia is a complex disorder characterized by positive, negative, and cognitive symptoms. Antipsychotic medications, which bind to dopamine D2 receptors (D2Rs), are effective at treating positive and negative symptoms. Adequate treatment for cognitive symptoms however, originating from aberrant hippocampal and prefrontal signaling, remains elusive. An emerging target in schizophrenia treatment is another member of the D2 family, the dopamine D3 receptor (D3R). Newly developed second-generation antipsychotics (SGAs) functioning as D3R agonists, such as cariprazine, show signs of cognitive symptom relief. Additionally, recent work from our lab has shown differential D3R signaling among different classes of SGAs in hippocampus CA1. Despite evidence implicating D3Rs in the treatment of schizophrenia cognitive symptoms, a clear understanding of hippocampal D3R expression and function remains unclear. Here I propose that within hippocampus CA1 dopamine D3Rs are the most widely expressed D2 family receptor and are a key mediator of hippocampal network function. Moreover, I will test the central hypothesis that D3Rs are the predominant D2 family receptor affecting hippocampal circuit function and that hippocampal D3R signaling is a core cellular mechanism of antipsychotic action. The effect of SGAs targeting the D2 family of receptors is often attributed to D2R action due to limited access differentiating between D2Rs and D3Rs. New pharmacology and in-situ approaches now allow for specific characterization of D2Rs and D3Rs. My preliminary data shows that significantly more CA1 cells express D3R transcripts than D2R. This indicates that D3Rs are the dominant D2 family receptor subtype in CA1, warranting further investigation of hippocampal D3R function. Indeed, my preliminary data demonstrates D3R agonism induces significant effects on excitatory and inhibitory synaptic transmission within CA1. Here, we will explore how D3Rs regulate both synaptic and intrinsic features of excitability in hippocampal circuits using electrophysiological and imaging approaches. Previous work from our lab has outlined a D3R specific mechanism of SGA axon initial segment calcium modulation in CA1 pyramidal cells. This modulation provides another avenue for D3Rs to alter CA1 spiking and hippocampal output in addition to changes in CA1 synaptic transmission. The diverse array of D3R mediated CA1 synaptic and firing properties could serve as potential sites for D3R specific SGA action. We will test this hypothesis through the pursuit of three aims. Aim 1: To determine the expression profile of SGA-targeted dopamine receptors in hippocampus CA1. Aim 2: To determine the mechanism by which dopamine D3 receptors regulate hippocampus CA1 function. Aim 3: To determine how SGAs affect dopamine D3 receptor-dependent hippocampus CA1 circuitry. We expect this work to uncover the cellular mechanisms of D3R activity in CA1 and the D3R specific actions of SGA treatment. This will not only advance our understanding of hippocampal dopaminergic signaling, but delineate cellular mechanisms of SGA action informing new therapeutic targets for treating schizophrenia cognitive symptoms. Project Number: 1F32MH140488-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Kevin Keary | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $76,780 | Activity Code: F32 | Study Section: Special Emphasis Panel[ZRG1 F03B-W (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11316643