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 and when Plxna2-GAP function is required during brain development to ensure normal behavior in adulthood.

Public Health Relevance

There is overwhelming evidence that neuropsychiatric disorders have a developmental origin. In recent years a large number of rare and common allelic variants have been identified that correlate with susceptibility to psychiatric disorders. The research described in this application is aimed at a deeper understanding of the basic biology and neural function of molecules identified by genetic studies. To study gene function, we employ a combination of biochemistry-based, mouse genetic, electrophysiological, anatomical and behavioral approaches. A better understanding of these processes will provide insights into gene function and associated biochemical pathways. Knowledge generated may be exploited for the development of new therapeutic strategies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1)
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Driscoll, Jamie
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University of Michigan Ann Arbor
Anatomy/Cell Biology
Schools of Medicine
Ann Arbor
United States
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