The impact of Tsc-mTOR signaling on cells and circuits in the basal ganglia

University Of California Berkeley, Berkeley CA

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Abstract

Significant progress has been made in identifying genetic factors contributing to autism spectrum disorder (ASD). Although ASD-risk genes have diverse biological functions, many of them are important for controlling the structure and function of synapses. We propose that a core feature of ASD, restricted, repetitive patterns of behavior, is caused by synaptic dysfunction in the basal ganglia, a brain region that controls the selection and learning of appropriate actions. Little is known about the mechanisms by which mutations in genes associated with ASD affect the basal ganglia. To address this, we will determine how disruption of the ASD-risk gene Tsc1 affects the cellular physiology and behavioral output of neurons comprising key basal ganglia circuits. To isolate specific cell types, we will use genetic mouse models in which Tsc1 is selectively deleted from defined cell populations. Our goal in Aim 1 is to investigate how Tsc1 loss affects intrinsic and synaptic excitability in the two classes of striatal projection neurons that initiate the primary output pathways of the basal ganglia. In addition, we will test the idea that synaptic alterations in striatal neurons lead to altered motor behaviors and increased propensity for habit formation. Striatal activity is dynamically regulated by dopamine signaling, which exerts a powerful control over basal ganglia-mediated behaviors. In Aim 2, we will determine how selective deletion of Tsc1 from dopamine neurons affect their physiology and output. Using behavioral experiments, we will test the hypothesis that altered dopamine signaling due to loss of Tsc1 leads to behavioral inflexibility. This strategy represents a key step towards defining the neural basis of ASD, which may ultimately inform the rational design of new therapeutic strategies for this disorder.