Underlying mechanisms in a cerebellum-dependent model of autism

  • Awarded: 2011
  • Award Type: Explorer
  • Award #: 232304

Considerable evidence suggests that changes to brain activity in the cerebellum are involved in autism spectrum disorder. In addition, disruption of a molecular pathway that controls protein synthesis — the mTORC1 pathway — has been implicated in the disorder. In a mouse model in which the mTORC1 pathway has been selectively disrupted in cerebellar neurons called Purkinje cells (PCs), the mice show numerous behaviors that are consistent with symptoms of autism.

Wade Regehr and his colleagues at Harvard Medical School plan to use electrophysiological approaches to determine the mechanisms underlying the behavioral abnormalities in these mice. Their goal is to gain insight into the cellular changes in the cerebellum, such as alterations to synapses, the junctions between neurons, that lead to behaviors associated with autism. They have designed studies to test the following hypotheses: (1) synaptic inputs to PCs are altered, leading to inappropriate PC activity, (2) the intrinsic excitability of PCs is altered, leading to inappropriate firing and (3) synaptic outputs from PCs are perturbed, thereby altering target-cell firing.

The researchers have begun to test these hypotheses and have already obtained preliminary data suggesting that intrinsic excitability of the PCs is altered. Extending these studies promises to provide new insights into the role of cerebellar PCs and the cognitive role of the cerebellum in autism spectrum disorder.

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