Cerebellar plasticity and learning in a mouse model of autism

  • Awarded: 2011
  • Award Type: Research
  • Award #: 203507

Christian Hansel and his colleagues at the University of Chicago examined whether memory mechanisms in the cerebellar cortex are affected in autism. They found that motor coordination and learning are impaired in a mouse model of 15q duplication syndrome, an autism spectrum disorder involving duplication of the chromosomal region 15q11-13. This copy number variant occurs in roughly 5 percent of autism cases and is the most prevalent cause of autism known to date.

The researchers have characterized cellular correlates of learning and memory, such as long-term depression (LTD) and long-term potentiation (LTP) at cerebellar synapses, the connections between neurons. These forms of synaptic plasticity — the ability of a synapse to change in strength in response to either use or disuse — are widely seen as crucial mechanisms for the synaptic memory that underlies associative learning in the cerebellum.

Hansel’s team measured motor coordination in the mice with a system called DigiGait, an imaging system that allows for analysis of motor parameters during treadmill running. They assessed motor learning via a delayed eye-blink conditioning task in which mice learn to associate a neutral stimulus (in this case, light) with a potentially harmful stimulus (air-puff directed to the eye; in collaboration with Samuel Wang’s lab at Princeton University).

Upon examination of the brains of the model mice, Hansel’s group observed ectopic climbing-fiber synapses on fine dendritic, or signal-receiving, branches of Purkinje cells. Under normal conditions, these synapses exclusively contact the primary dendrite. They also saw enhanced transmission at these synapses, and impaired cerebellar LTD — the presumed cerebellar correlate of motor learning.

Finally, they found enhanced expression of UBE3A, the protein mutated in the autism-related disorder Angelman syndrome. It is possible that this change in UBE3A expression affects climbing-fiber synapse stabilization, and ultimately LTD and motor learning. Hansel and his colleagues plan to continue to examine these causal relationships.

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