Disruption of basal ganglia maturation by cortical hyperactivity in the Shank3 mouse model of autism
- Awarded: 2019
- Award Type: Bridge to Independence
- Award #: 491357
While the neural substrates and pathophysiological mechanisms underlying the onset of cognitive and motor deficits in autism spectrum disorder (ASD) remain unclear, research suggests that aberrant corticostriatal development may play a role. Mutations in ASD-associated Shank3 in mice (Shank3B–/-) result in hyperactivity of cortical circuits and accelerated maturation of corticostriatal connectivity during postnatal development1,2. Importantly, behavioral abnormalities in Shank3B–/-mice emerge during this developmental stage, suggesting that abnormal postnatal development of corticostriatal circuits might be implicated in the onset of behavioral deficits in Shank3B–/- mice.
The goal of Rui Peixoto’s current project is to address how basal ganglia striatal circuits adapt to cortical hyperactivity during different periods of development and how abnormal basal ganglia maturation may contribute to the emergence of repetitive behaviors and motor stereotypies in ASD, using the Shank3B–/- ASD mouse as a model system. This work will advance our basic understanding of the mechanisms regulating corticostriatal circuit development and provide insight regarding a potential common pathophysiological mechanism in ASD.
- The influence of ASD risk genes on corticostriatal circuit development and reinforcement learning
- Striatal circuit dysfunction in a mouse model of the autism risk gene CACNA1D
- The influence of ASD-risk genes on synaptic function in the basal ganglia
- Identifying convergent cortical circuit impairments across multiple mouse models of autism