Linking cortical circuit dysfunction and abnormal behavior in genetic mouse models of autism

  • Awarded: 2014
  • Award Type: Targeted: Circuit Dynamics
  • Award #: 295438

Carlos Portera-Cailliau plans to investigate how brain circuits are altered in animal models of autism and intellectual disability. Portera-Cailliau and his colleagues at the University of California, Los Angeles (UCLA) aim to use state-of-the-art microscopy techniques to study brain areas that, in experimental models of autism, are important for emotion, cognition, creativity, learning and memory. The group’s experiments are designed to provide insight into how subtle alterations in brain wiring and connectivity can result in neuropsychiatric disorders such as autism.

Specifically, the researchers aim to test the hypothesis that defects in network connectivity at the level of the cerebral cortex directly lead to symptoms of autism, learning disability, language delay and intellectual dysfunction. Portera-Cailliau and his collaborator at UCLA, Peyman Golshani, have identified specific alterations in neuronal excitability in animal models of two prototypical autism spectrum disorders: fragile X syndrome and cortical dysplasia-focal epilepsy syndrome (CDFE).

The group now plans to investigate how missing FMR1 — the gene affected in fragile X syndrome — and missing CNTNAP2, which is mutated in CDFE, can disrupt sensory processing. Using a circuit-to-symptom approach that attempts to link alterations in neuronal circuits to impaired sensory processing and other autism symptoms, they will address the following important questions: Is there evidence for abnormal sensitivity to sensory inputs in autism model mice? Do mutations in FMR1 or CNTNAP2 also cause alterations in the cortical network ensemble dynamics that underlie sensory discrimination? Can modulating neuronal excitability correct such network defects and rescue behavioral performance?

Overall, the experimental design exploits cutting-edge in vivo imaging techniques and seeks to address important knowledge gaps in autism pathogenesis.

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