Screening for convergence of axonal dysfunction across diverse mouse models of autism

  • Awarded: 2019
  • Award Type: Research
  • Award #: 633450

The neural mechanisms that underlie the cognitive and behavioral deficits in autism spectrum disorders (ASDs) are not well understood at the circuit level, although there is converging evidence from several mouse models for altered synaptic function. There is less evidence supporting altered intrinsic neural excitability.

John Huguenard’s laboratory has recently studied cortical excitability in two mouse models of ASD arising from environmental insult during prenatal development via maternal immune activation. Preliminary findings indicate that, in the medial prefrontal cortex (mPFC), a site of higher-order executive function, there is a structural and functional disorganization of axons and the axon initial segment, a specialized axonal region in which action potentials are initiated. This axonal dysfunction results in impaired action potential output of mPFC neurons that would limit the ability of the mPFC to communicate with other brain regions and fulfill its role in cognition and social behavior.

To test whether this specific alteration in mPFC output axons is a point of biological convergence in ASD, Huguenard’s team plans to use a focused electrophysiological and imaging approach to test for mPFC axonal dysfunction in an additional environmental insult mouse model (i.e., induced by gestational exposure to valproic acid) and in three distinct genetic mouse models of ASD (i.e., mice with disruptions in Shank3, Cntnap2 and Gabrb3).

The team will first utilize high-throughput multielectrode recordings of mPFC activity in brain slices to assess overall mPFC excitability, including assays they have developed to specifically probe for altered axonal function. Huguenard’s laboratory has previously shown this approach to be highly effective in highlighting specific circuit subcomponents worth further, more refined assessments with lower throughput methods. Subsequent to this initial high-throughput approach, the team will use more refined methods, such as single-cell electrophysiology and soma/axon paired recordings enabled by two-photon microscopy to probe the neural circuitry in greater detail. Finally, in the third step, these electrophysiological studies will be complemented by structural analysis of axons and axon initial segments using automated 3-D image analysis of axon initial segments and reconstruction of individual axon trajectories using Neurolucida.

The results of the proposed experiments are expected to show whether mPFC axonal hypofunction contributes to ASD-related pathologies in subsets of etiological classes specifically or more broadly. Overall, these studies will lead to an improved understanding of ASD pathogenesis involving a variety of genetic and environmental insults.

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