Characterization of striatal dopamine dynamics in Shank3-/- mice during postnatal development

Autism spectrum disorders (ASD) are neurodevelopmental conditions marked by early-emerging deficits in social behavior, restricted interests, and motor abnormalities. Converging genetic and clinical evidence implicates dysfunction of the dopaminergic (DA) system as a core feature of ASD pathophysiology. DA signaling is essential for the maturation of striatal circuits, which govern reward processing, motor learning, and emotional regulation. However, the developmental origins of dopaminergic dysfunction in ASD, and how genetic risk factors affect striatal DA signaling in vivo during early life, remain unknown. Mutations in SHANK3 are among the most penetrant genetic causes of ASD, and Shank3-deficient mice exhibit early striatal circuit abnormalities, impaired social behavior, and DA neuron dysfunction. Preliminary evidence suggests that loss of Shank3 disrupts DA neuron excitability and alters dopamine release dynamics in the nucleus accumbens (NAc) during ethologically relevant behaviors. However, technical challenges have historically limited in vivo monitoring of DA signaling in developing mouse pups, preventing direct investigation of this hypothesis. To address this gap, we have developed a novel fiber photometry platform optimized for postnatal mice (~P15) using tapered optical fibers, enabling stable, high-resolution recordings of striatal DA dynamics and neural activity during maternal and social interactions. We will combine this in vivo imaging approach with whole-cell electrophysiology and genetic tools to define the impact of Shank3 loss on the maturation of dopaminergic circuits. Aim 1 will quantify in vivo DA signaling in the NAc of P15 Shank3-/- and conditional DA neuron-specific Shank3 knockout mice during maternal and social interaction paradigms. Aim 2 will assess intrinsic excitability and HCN channel function in VTA DA neurons projecting to the NAc, comparing global and DA neuron-specific Shank3 knockouts to isolate cell- autonomous mechanisms of dysfunction. Together, these studies will provide the first real-time characterization of postnatal DA circuit dynamics in a genetically validated ASD model and identify a mechanistic link between Shank3 loss, HCN channel dysfunction, and DA signaling abnormalities. The proposed work will not only establish an innovative platform for studying DA function in early development but also define therapeutic targets for SHANK3-related disorders and other forms of ASD with disrupted striatal dopamine signaling. Project Number: 1R21MH141315-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Rui Peixoto | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $437,250 | Activity Code: R21 | Study Section: Developmental Brain Disorders Study Section[DBD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11371849