Defects of cortical cell migration have been linked to a spectrum of phenotypes that include epilepsy, mental retardation, autism, and schizophrenia (SZ). In the past, functional analyses of human genes linked to classic disorders of neuronal migration have yielded valuable insights into the pathways involved in migration and the underlying causes of these diseases. Studies in rodents have added additional factors to the list of genes necessary for migration. One such factor is Amyloid Precursor Protein (APP), an Alzheimer's Disease linked gene, which is required for both normal migration into the cortical plate and neuronal process outgrowth. In addition, several genes have been linked to schizophrenia such as D1SC1, PDE4, and NRG1, all of which play important roles in neuronal development, including migration and neurite outgrowth. Recent studies link classic pathways of migration involving factors such as AP0ER2, DAB1, and LIS1 with both APP and certain SZ-linked genes. This proposal aims to 1) integrate these newly identified players into established migration and neurite outgrowth pathways;2) elucidate how certain mutations and variants in SZ-associated genes lead to defects in migration;and 3) address whether defects in migration and/or subtle alterations in neuronal process outgrowth lead to altered levels of neurotransmitters and their receptors, both of which are described in patients with SZ. The in vivo method of in utero electroporation will be used to express shRNAs or cDNAs encoding wild type or mutated versions of candidate proteins to assess the effects of their altered expression on neuronal precursor migration in the context of the embryonic rat brain. Primary neuronal cultures also will be utilized to analyze the effects of these various constructs on neuonal process outgrowth. Lastly, both neurotransmitter receptor expression (using biochemistry and immunohistochemistry) and neurotransmitter levels (using microdialysis and HPLC) will be analyzed in rodents in which different genetic manipulations have caused varying degrees of disordered cortical migration. This set of experiments will address the hypothesis that abnormalities in neuronal migration are linked to defects in the neurotransmitter systems that are observed in patients with SZ.

Public Health Relevance

Psychiatric disorders such as schizophrenia and autism have been linked to developmental processes such as cortical cell migration and neuronal process outgrowth. This proposal aims to understand normal and abnormal neuronal development through analyses of the functions and mechanisms of genes linked to these disorders in humans, with the ultimate goal of identifying novel molecular targets for drug discovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Transition Award (R00)
Project #
5R00MH085004-05
Application #
8470230
Study Section
Special Emphasis Panel (NSS)
Program Officer
Panchision, David M
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$226,418
Indirect Cost
$99,573
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Rice, Heather C; Young-Pearse, Tracy L; Selkoe, Dennis J (2013) Systematic evaluation of candidate ligands regulating ectodomain shedding of amyloid precursor protein. Biochemistry 52:3264-77
Taniguchi, Yu; Young-Pearse, Tracy; Sawa, Akira et al. (2012) In utero electroporation as a tool for genetic manipulation in vivo to study psychiatric disorders: from genes to circuits and behaviors. Neuroscientist 18:169-79