# Muscarinic Receptor Activators as Antipsychotic Agents

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2022 · $502,014

## Abstract

Recent clinical and preclinical studies suggest that highly selective positive allosteric modulators
(PAMs) for specific muscarinic acetylcholine receptor (mAChR) subtypes have exciting potential as novel
treatments for positive symptoms, negative symptoms, and cognitive disturbances in patients suffering from
schizophrenia. However, the precise mechanisms by which mAChRs regulate brain circuits that are relevant
for the major symptom clusters associated with schizophrenia are unknown. It will be critical to develop a full
understanding of the precise cellular and circuit roles of each mAChR subtype that could be relevant for
schizophrenia and related brain disorders. Early stages of schizophrenia are associated with hyperactivity of
the prefrontal cortex (PFC) and this is important for some of the cognitive and negative symptoms associated
with the disease. Interestingly, we have found activation of the M1 subtype of mAChR induces long-term
depression (M1-LTD) of transmission at excitatory synapses in the PFC, and also induces a robust increase in
inhibitory transmission in this region. These combined actions could contribute to the established ability of
highly selective M1 PAMs to reverse cognitive deficits in rodent models that are relevant for schizophrenia.
Based on previous and new preliminary studies, we postulate that M1-LTD and M1-induced increases in
synaptic inhibition in the PFC are mechanistically distinct and depend on activation of M1 in different neuronal
populations. Specifically, we postulate that M1-LTD is mediated by activation phospholipase D (PLD) in PFC
pyramidal cells, and that M1 increases inhibitory transmission through direct excitatory effects on specific
populations of inhibitory interneurons through a PLD-independent mechanism. We propose a series of studies
in which we will selectively delete M1 from specific neuronal populations and use M1 PAMs that differentially
regulate coupling of M1 to PLD and phospholipase C (PLC), along with optogenetic silencing of specific
neuronal populations, to rigorously evaluate the roles of M1 expressed in each of these major neuronal
populations. Specifically, we will test the hypothesis that M1 PAMs induce M1-LTD by actions on M1 expressed
in PFC pyramidal cells and do not require activation of M1 in inhibitory neurons (Aim 1). We will then perform
a series of studies to test the hypothesis that M1 activation increases inhibitory transmission in the PFC by
actions on defined populations of inhibitory interneurons (Aim 2). Finally, we will take advantage of our range
of genetic, optogenetic, and pharmacological tools to test the hypothesis that M1 PAMs reverse deficits in
specific behavioral measures of cognitive function by actions on different neuronal populations in the PFC
(Aim 3). These studies will provide important new insights into the cellular and circuit mechanisms by which
M1 PAMs enhance and restore deficits in specific domains of cognitive function that could be critic...

## Key facts

- **NIH application ID:** 10359126
- **Project number:** 5R01MH073676-17
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Jerri Michelle Rook
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $502,014
- **Award type:** 5
- **Project period:** 2006-01-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359126

## Citation

> US National Institutes of Health, RePORTER application 10359126, Muscarinic Receptor Activators as Antipsychotic Agents (5R01MH073676-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10359126. Licensed CC0.

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