Striatal cholinergic interneurons (SCINs) are implicated in several pathologies involving the basal ganglia, including motor and neuropsychiatric disorders. They are key modulators of striatal circuit function at both pre- and postsynaptic level, regulating corticostriatal synaptic transmission/plasticity and striatal neuron excitability. We have recently characterized a mouse model of autism spectrum disorder (ASD) obtained by the targeted deletion of the ASD-linked Tshz3 gene in cholinergic neurons (Chat-cKO): these mice show repetitive and restricted behaviors (RRBs) paralleled by a significant decrease of SCIN firing frequency and regularity, and an increased proportion of these cells in the striosome compartment vs. the matrix. Here, we examined the consequence of SCINs’ dysfunction on striatal circuit, which could underlie the RRBs characterizing this ASD model. We focused on striatal spiny projection neurons (SSPNs) that represent >90% of the striatal neuronal population and are key targets of SCIN-mediated cholinergic modulation. Our preliminary electrophysiological data (slice patch-clamp) show decreased SSPN excitability in Chat-cKO mice due to a lower basal stimulation of M1 receptors, supporting the hypothesis of decreased cholinergic tone. Ongoing experiments examine the respective changes in D1 and D2 SSPNs. Moreover, since boosting striatal cholinergic neurotransmission restores SSPN excitability on slice, we are testing whether such approach in vivo (donepezil treatment or SCIN activation by DREADD) can improve RRBs in Chat-cKO mice. These findings offer novel insight on the pathogenesis of RRBs associated to ASD, and may provide proof of concept for potential pharmacological treatments to improve these symptoms by a drug repurposing strategy.