Investigation of social brain circuits in mouse models of the 16p11.2 locus

  • Awarded: 2011
  • Award Type: Pilot
  • Award #: 204719

In recent years, autism heritability has been the focus of intense research, and a number of autism susceptibility genes and loci have been identified. This progress has allowed researchers to generate mouse models that carry relevant mutations, providing a biological system for dissecting the circuit, cellular and molecular mechanisms underlying autism-associated changes in brain development.

Over the past two years, Pavel Osten’s team at Cold Spring Harbor Laboratory in New York has focused on the development of an automated method called serial two-photon (STP) tomography, which integrates two-photon microscopy and tissue sectioning to achieve high-throughput fluorescence imaging of whole mouse brains. The researchers established this method for whole-brain tracing of neural connections and mapping of brain activation related to genetic expression.

Osten and his colleagues are studying the brain circuits of mice engineered to carry either the deletion or reciprocal duplication of a chromosomal region homologous to the human 16p11.2 locus, one of the best-characterized genetic regions associated with autism. They plan to use whole-brain screening by STP tomography to search for brain areas and circuits with abnormal activation during social behavior and in response to an imbalance of brain excitation and inhibition.

These studies may be complemented with anatomical, immuno-histochemical and electrophysiological experiments that can determine cell types and analyze intrinsic and synaptic properties of neurons in the brain regions of interest. The combination of brain-wide and region-specific methods should enable the researchers to identify autism-relevant functional and structural changes in the mouse brain. Their ultimate goal is to use the results to formulate hypotheses for the development and testing of therapeutic strategies for autism and related neurodevelopmental disorders.

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