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.

Public Health Relevance

Autism spectrum disorders (ASDs) are among the most heritable human diseases. Our goal is to identify causal links between autism susceptibility genes and neural circuit deficits in genetic mouse models of autism. We hope that this work will identify candidate brain regions and circuits for detailed mechanistic studies and therapeutic development.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH096946-03
Application #
8645760
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Anderson, Kathleen C
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Takada, Naoki; Pi, Hyun Jae; Sousa, Vitor H et al. (2014) A developmental cell-type switch in cortical interneurons leads to a selective defect in cortical oscillations. Nat Commun 5:5333
Osten, Pavel; Margrie, Troy W (2013) Mapping brain circuitry with a light microscope. Nat Methods 10:515-23