STRIATAL PATHWAYS SPECIFICITY IN THE REGULATION OF ANXIETY AND COMPULSIONS IN THE OBSESSIVE-COMPULSIVE DISORDERS MODEL SAPAP3-KO

Mice lacking SAPAP3 exhibit excessive grooming, a hallmark of compulsive behavior. While restoring SAPAP3 expression in the striatum reverses this phenotype (Welch, 2007), the specific contribution of this protein within striatal subcircuits to the generation of compulsions remains unclear. The striatum contains two main spiny projection neuron populations—the direct and indirect pathways—with opposite and complementary roles in motor control and behavior (Gerfen & Surmeier, 2012; Kravitz et al., 2010). In the SAPAP3-KO model, optogenetic inhibition of the indirect pathway in the dorsomedial striatum reduces excessive grooming (Ramírez-Armenta et al., 2022), whereas hyperactivity of this pathway promotes compulsive behavior (Piantadosi et al., 2024). Exacerbated activity of the direct pathway has also been suggested as a substrate of compulsions (Lee et al., 2024). To dissect the specific contributions of each pathway to compulsive and anxiety behaviors, we developed a viral vector enabling Cre-dependent SAPAP3 expression. Using double transgenic mice (Sapap3-KO::A2A-Cre or Sapap3-KO::D1-Cre), we selectively restored SAPAP3 in the indirect or direct pathways. Early postnatal restoration was performed, allowing protein expression for two months before behavioral testing. Open-field, elevated plus-maze, and neuronal activity recordings using head-mounted microendoscopes and GCaMP were performed in freely moving mice. Our results show that restoring SAPAP3 in the direct pathway further increases excessive grooming, while restoring it in the indirect pathway reduces anxiety-like behaviors without affecting grooming. Calcium imaging analysis revealed that restoring SAPAP3 in the indirect pathway alters neuronal dynamics, with changes in both the amplitude and frequency of calcium transients.