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Dissecting the circuity basis of autistic-like behavior in mice

Guoping Feng, Ph.D.
Massachusetts Institute of Technology

The neurobiology behind the classic signs of autism — repetitive behaviors, impaired social interactions and language deficits — is largely unknown. Based on their studies on mouse models of obsessive compulsive disorder and autism, Guoping Feng and his colleagues at Massachusetts Institute of Technology propose that abnormal signaling between neurons in the cortex and those in the striatum underlies the behaviors associated with autism.

Neurons send information to each other via stereotypical paths known as neural circuits to control behavior and body movements, among other processes. For example, many neurons of the cortex signal to neurons of the basal ganglia, which integrate this information into a single output. The neurons of the basal ganglia then signal to the neurons of the thalamus, allowing the action to begin. This neural circuit controls the initiation of most movements, simple to complex. Defects in this circuit have been strongly implicated in autism.

Feng and his colleagues plan to pinpoint the neuronal signaling defects in these circuits that lead to repetitive behavior and poor social behavior in mice. In previous studies, the researchers observed these behaviors in mice with a disruption of the PSD95-SAPAP3-SHANK3 scaffolding complex. In neurons of the basal ganglia, this complex anchors the proteins that receive signals from a neuron in the cortex.

Using SHANK3-deficient mice to disrupt the scaffolding complex, the researchers plan to disturb neuronal signaling in basal ganglia circuits by combining genetic, optogenetic, electrophysiological and behavioral approaches. Based on these experiments, the researchers hope to learn how abnormal signaling between neurons in the cortex and in the striatum lead to autism-like behaviors.

These studies may significantly enhance our understanding of neural circuitry mechanisms of repetitive behavior and impaired social interactions, and help to develop novel strategies for more effective treatment.