Cell adhesion molecules in autism: a whole-brain study of genetic mouse models

Summary

Principal Investigator: Pavel Osten
Abstract: DESCRIPTION (provided by applicant): Autism comprises a spectrum of highly heritable disorders and today the relevant susceptibility genes are being identified by large scale genomics projects. An important outcome of the identification of autism genes is the possibility to use genetic mouse models to study circuit, cellular and molecular mechanisms by which these genes affect brain development and function. The current project is focused on three mouse models carrying mutations in cell adhesion molecules (CAMs): the neuroligin 3 R451C, neuroligin 4 null, and Cntnap2 null mice. These mice were selected as representatives of a larger family of synaptic genes linked to autism, which includes neuroligins, neurexins, Cntnap, cadherin, contactin, and Shank proteins. The identification of rare mutations in these genes provides a strong support for the role of synaptic maturation and function in autism. The current proposal aims to begin to dissect the underlying circuit and cellular mechanisms in the three mouse models. In order to be able to compare brain functions in different autism mouse models, we have developed a novel method for high-throughput imaging of whole mouse brains. This method, which we call serial two- photon (STP) tomography, integrates two-photon laser-scanning microscopy and tissue sectioning. To study brain functions by STP tomography, we use transgenic c-fos-GFP mice that express green fluorescent protein (GFP) as a reporter for the induction of the immediate early gene c-fos. This allows us to identify brain regions with abnormal c-fos induction, and by extension neural activation, evoked during behavioral tasks or by systemic drug applications. Such abnormal regions-candidate brain areas for autism-related pathology-then become the focus of detailed electrophysiological and anatomical studies, which aim to determine the exact underlying circuit and cellular mechanisms. The Specific Aims are: 1. To study how CAM mutations affect brain circuits mediating social behavior. 2. To study how CAM mutations affect oscillatory cortical activity and the balance of brain excitation and inhibition. 3. To study anatomical connectivity and cellular physiology of candidate brain regions. We believe that a successful completion of the proposed experiments will provide mechanistic insights into neurodevelopmental changes in brain functions that lie downstream of the synaptic genes in autism. Our ultimate goal is to use such results to formulate hypotheses for the development and testing of therapeutic strategies in the future.
Funding Period: 2012-04-01 - 2017-03-31
more information: NIH RePORT

Top Publications

  1. pmc Mapping brain circuitry with a light microscope
    Pavel Osten
    Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
    Nat Methods 10:515-23. 2013

Research Grants

  1. Defining and Treating Written Language Disabilities
    VIRGINIA WISE BERNINGER; Fiscal Year: 2013
  2. A neuroimaging study of twin pairs with autism
    ANTONIO YOUSSEF HARDAN; Fiscal Year: 2013
  3. Functional Analysis of Rare Variants in Genes Associated with Autism
    Ellen J Hoffman; Fiscal Year: 2013
  4. FUNCTION OF NEUREXINS
    Thomas C Sudhof; Fiscal Year: 2013
  5. Frontostriatal Synaptic Dysfunction in a Model of Autism
    PATRICK ROTHWELL; Fiscal Year: 2013
  6. SRC on Primary Tumors of the CNS
    Darell D Bigner; Fiscal Year: 2013
  7. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
  8. Neuroligin Function in vivo: Implications for Autism and Mental Retardation
    Craig M Powell; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc Mapping brain circuitry with a light microscope
    Pavel Osten
    Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
    Nat Methods 10:515-23. 2013
    ..We present an overview of the present state and future opportunities in charting long-range and local connectivity in the entire mouse brain and in linking brain circuits to function...

Research Grants30

  1. Defining and Treating Written Language Disabilities
    VIRGINIA WISE BERNINGER; Fiscal Year: 2013
    ..The proposed multidisciplinary research has practical significance for improving diagnosis and providing more effective services which may lower such risks. ..
  2. A neuroimaging study of twin pairs with autism
    ANTONIO YOUSSEF HARDAN; Fiscal Year: 2013
    ..A better understanding of the pathophysiology of autism will be instrumental in the development of effective therapeutic strategies that aim at targeting the core symptoms of social and communication deficits. ..
  3. Functional Analysis of Rare Variants in Genes Associated with Autism
    Ellen J Hoffman; Fiscal Year: 2013
    ..Hoffman[unreadable]s goal of elucidating the molecular and cellular mechanisms of ASD. ..
  4. FUNCTION OF NEUREXINS
    Thomas C Sudhof; Fiscal Year: 2013
    ..Results from this project will not only provide insight into how neurons communicate, but also promote our understanding of how such communication becomes dysfunctional in autism and schizophrenia. ..
  5. Frontostriatal Synaptic Dysfunction in a Model of Autism
    PATRICK ROTHWELL; Fiscal Year: 2013
    ..abstract_text> ..
  6. SRC on Primary Tumors of the CNS
    Darell D Bigner; Fiscal Year: 2013
    ..Cores A and C are currently funded;Core B is a continuation from earlier grant periods. ..
  7. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  8. Neuroligin Function in vivo: Implications for Autism and Mental Retardation
    Craig M Powell; Fiscal Year: 2013
    ..3. To determine whether deletion of NL3 or NL3 disease-linked mutations alter the threshold for inducing NMDA-receptor-dependent synaptic plasticity in the hippocampus. ..