Disrupted network activity in neonatal cortex of autism mouse models

  • Awarded: 2014
  • Award Type: Research
  • Award #: 308450

The etiology of autism is complex and mysterious. Autism has a strong genetic basis but there is remarkable diversity and heterogeneity in genes that are associated with the disorder. Despite this heterogeneity, a convergence of evidence suggests that disruptions in synapse function, neuronal activity and circuit formation are the origin of behaviors associated with autism.

Michael C. Crair and his colleagues aim to test the hypothesis that abnormal neuronal activity in the newborn brain leads to the emergence of abnormal functional connectivity that is the root cause of autism. This model reasons that genetic disruptions associated with autism produce profound alterations in ongoing activity in the early developing brain, potentially before overt behavioral symptoms are observed.

This altered early brain activity causes neural circuit wiring defects through errors in Hebb-like mechanisms — changes in synaptic connections as a result of their mutual correlated activity, leading to the formation of memories or learned behavior — or related activity-dependent mechanisms. In this model, Crair and his group hypothesize that the diversity in genes associated with autism produce the heterogeneity of symptoms due to the spectrum of deficits in early neuronal activity that affect the wiring of neurons and circuits in the developing brain.

The researchers employ in vivo techniques to optically image neuronal activity using genetically encoded calcium indicators across the entire neonatal mouse cortex. Ongoing spontaneous neuronal activity in the newborn mouse cortex is highly dynamic, but is repetitive and changes predictably with development. Preliminary experiments indicate that this activity, imaged live and noninvasively in an unanesthetized and mobile animal, is altered in mouse models of autism. These experiments are directly testing the hypothesis that disruptions in the neonatal brain produce neural circuit wiring defects that lead to autism-associated behaviors.

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