Rapid screening for cortical circuit dysfunction in autism-related mouse models

  • Awarded: 2014
  • Award Type: Explorer
  • Award #: 306752

Autism spectrum disorders are genetically heterogeneous, but whether they share a common neural circuit-processing defect is unclear. One emerging hypothesis is that the ratio of excitation to inhibition in the brain’s cerebral cortex is elevated in people with the autism, leading to hyperexcitability of neural circuits, impaired information processing, increased seizure risk and hypersensitivity to sensory stimuli.

Daniel Feldman and his colleagues at the University of California, Berkeley, aim to rapidly and quantitatively measure neural circuit function across multiple transgenic mouse models of autism and to test whether common modes of circuit dysfunction occur.

Feldman and his team plan to use high-throughput behavioral, neurophysiological and neural imaging methods to correlate neuronal activity, excitation-inhibition ratio and sensory perception in individual animals. They plan to focus on the primary somatosensory cortex, where circuit function is well understood. Processing disorders in this area may relate to tactile hypersensitivity, which is common in autism.

The researchers seek to establish the efficacy of this combined behavioral-neurophysiological-imaging approach by initially studying three mouse strains: mice lacking FMRl or CNTNAP2 and those lacking one copy of TSC2. These mice model the autism-related disorders fragile X syndrome, autism and tuberous sclerosis complex, respectively. Because each of these mouse strains can be tested rapidly, the team hopes to ultimately expand the approach to more than ten mouse models of syndromic and non-syndromic autism, in an effort to test whether common motifs of circuit dysfunction occur.

If shared circuit defects exist, this may enable a search for broadly effective therapies that restore circuit function across multiple forms of autism. The methods developed here could be applied to efficiently screen for therapeutic approaches that restore circuit function and ameliorate sensory abnormalities in people with the disorder.

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