Investigation of dopamine signaling pathways in medium spiny neurons

The National Institute of Mental Health awarded $165,656 to the Regents of the University of Colorado (University of Colorado-Denver) on December 26, 2025, under the Mental Health Research Grants program (CFDA 93.242, Assistance Listing designation F30MH141917) to investigate dopamine signaling pathways in medium spiny neurons as they relate to schizophrenia treatment.

The research project will use whole-cell patch-clamp electrophysiology and two-photon imaging to define how membrane-delimited and intracellular signaling respond to dopamine in D2-type medium spiny neurons, then examine whether clinically effective and ineffective antipsychotics antagonize these pathways with differential potency. The work addresses a fundamental gap in antipsychotic drug development: despite 70 years of D2 receptor antagonist use, limited understanding of how neurons encode phasic dopamine signaling has stalled discovery of pathway-specific therapies with improved efficacy and side-effect profiles. The project proposes that dysregulated phasic dopamine release onto D2 medium spiny neurons drives the positive symptoms of schizophrenia by encoding internal stimuli as salient.

Performance is located in Aurora, Colorado. The award period runs through June 30, 2029. This is a Project Grant, the standard assistance type under NIMH's Mental Health Research Grants program, supporting specified project periods not to exceed five years with potential renewal as a new competing request.

Abstract

Schizophrenia is a mental health disorder characterized by delusions, hallucinations, disorganized speech, and social dysfunction. IT is caused by dysregulated dopamine signaling onto D2-type medium spiny neurons (msns). Specifically, dopamine can be released after burst firing of the neuron, which induces phasic release. Phasic dopamine release is elicited during reward prediction as well as in response to salient stimuli, and in schizophrenia, phasic release is aberrantly elicited. This results in the encoding of internal stimuli as salient, leading to the positive symptoms of schizophrenia. Nearly all antipsychotics antagonize the D2 receptor. However, despite their wide use since the 1950S, drug discovery has been halted for the past 70 years. This is because (1) we have limited understanding of how neurons encode phasic dopamine signaling, thereby limiting the pathway specificity and efficacy of newly created drugs, and (2) little is known about how our current antipsychotics change that signaling. Preliminary data in the lab has shown that upon dopamine release and D2 receptor activation, g proteins can engage in membrane-delimited signaling or intracellular signaling with different potencies. However, IT is unknown whether these pathways are important for encoding phasic release, and whether clinically effective and effective antipsychotics antagonize either pathway with different potencies. This proposal addresses these two knowledge gaps by defining which postsynaptic pathways are activated by dopamine physiologically, and how clinically effective and ineffective antipsychotics change postsynaptic signaling in a biased manner. In aim 1, whole cell patch-clamp electrophysiology and 2-photon imaging will be used to define the sensitivity of membrane-delimited and intracellular signaling to dopamine in D2 msns. In aim 2 builds off aim 1 by examining whether clinically effective and ineffective antipsychotics selectively target these different signaling pathways. Altogether, results from the proposed experiments will allow US to define the pathways necessary for physiologic functioning, how they change in schizophrenia, and as a result which pathways must be targeted for effective treatment. Furthermore, completion of these aims will allow me to gain neuropharmacology expertise, improve my technical skills in electrophysiology and 2-photon imaging, and learn to test rigorous hypotheses applicable to my clinical interests. The training provided and skills enhanced by this proposal will be invaluable for my becoming a psychiatrist with a focus on translating basic neuroscience research into novel therapies for mental health disorders.