# Inhibitors of Synaptogenesis and Mental Health

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $496,068

## Abstract

Mounting evidence suggests that many neuropsychiatric disorders have a developmental origin with a strong
genetic underpinning. A large number of allelic variants has been identified that associate with mental illness.
While genetic discoveries are a crucial first step, the next major challenge is to define the biochemical
pathways altered by disease alleles and to develop a more nuanced understanding of how these dysfunctional
pathways disrupt brain function relevant to disease symptomatology. Of interest, mutations in members of the
SEMAPHORIN (SEMA) family of axon guidance molecules, and their receptors, the PLEXINS (PLXN) carry
varying genetic risks for mental illness. Allelic variants of SEMA5A and its receptor PLXNA2 associated with
mood disorders cause reduced gene expression. To explore the underlying biology of how reduced
SEMA5A/PLXNA2 expression may contribute to mental illness, we use Plxna2 transgenic mice as an
experimental system. Morphological studies with Sema5a and Plxna2 mutant mice identified distinct
anatomical phenotypes: defects in migration of early-born dentate granule cells (GCs) progenitors from the
primary neuroepithelium to the dentate gyrus (DG) and an increase in spine synapse density in mature GCs in
the DG. Adult Plxna2 mice exhibit gene-dosage and sex-specific behavioral defects in episodic memory,
sensorimotor gating, and sociability; traits commonly observed in psychiatric disorders including
Schizophrenia. For a deeper understanding of how Plxna2 deficiency may contribute to behavioral phenotypes,
we used gene editing to disrupt the GTPase-activating protein (GAP) domain in the PlxnA2 cytoplasmic region.
Loss of PlxnA2-GAP enzymatic activity impairs Rap1-GTPase dependent GC progenitor migration and leads to
supernumerary spine synapses in mature GC. Moreover, PlxnA2-GAP deficiency disrupts episodic memory
and sensorimotor gating. To probe deeper into how impaired Sema5A/PlxnA2-GAP/Rap1 signaling leads to
behavioral defects, we used a proteomics-based approach and identified novel PlxnA2 interacting proteins. In
the current application we propose a multidisciplinary approach comprised of recently developed biochemical
tools, electrophysiological techniques, conditional gene ablation and mouse behavior. SPECIFIC AIM 1 is
aimed at the characterization of novel mechanisms that regulate Sema5A-PlxnA2 signaling, including the
guanine nucleotide exchange factors (GEFs) that antagonize PlxnA2-GAP activity. SPECIFIC AIM 2 builds on
our observation that forebrain specific ablation of Plxna2 mimics behavioral defects observed in Plxna2
germline null mice. We pursue a mouse genetic approach to identify developmental epochs of vulnerability
and the neural substrate associated with impaired behaviors in Plxna2-/- and Plxna2-GAP deficient mice.
Genetic studies will be complemented by electrophysiological recordings, histological analyses and high-
resolution magnetic resonance imaging. Studies are aimed at determining where ...

## Key facts

- **NIH application ID:** 10468640
- **Project number:** 5R01MH119346-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Roman Jeno Giger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $496,068
- **Award type:** 5
- **Project period:** 2019-09-24 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468640

## Citation

> US National Institutes of Health, RePORTER application 10468640, Inhibitors of Synaptogenesis and Mental Health (5R01MH119346-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10468640. Licensed CC0.

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