ORIGINAL

Abstract

Disruptive and excessive repetitive behaviors occur in several neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorder, obsessive compulsive disorder, anxiety disorders, and advanced stages of addiction. Studies in both rodents and humans have implicated dorsal striatum dysfunction in pathologies showing a lack of behavioral flexibility. Ongoing work in our lab has aimed to characterize structural and functional differences in mechanisms of plasticity in the dorsal striatum of four mouse models that show excessive repetitive behavior. Across these four models with diverse etiologies (one inbred, two transgenic, and one prenatal toxin exposure), we found consistent over-expression of perineuronal nets (PNNs) surrounding PV+ interneurons in the dorsomedial striatum, a region known to be important for action-outcome association learning. We then conducted behavioral and ex vivo electrophysiology studies in one of these models, an inbred mouse strain BTBR T+Itpr3tf/J (BTBR). We found impairments in DMS-dependent associative learning, maladaptive excessive grooming, and excessive non-goal-oriented digging. These behavioral deficits were accompanied by a baseline increase in DMS inhibitory signaling. These results led us to hypothesize that excessive repetitive behaviors are driving an increase in PNNs in the dorsal medial striatum, and the resulting increase in network rigidity further exacerbates the excessive repetitive phenotype and impairing other DMS-related functions. We found that reduction of DMS PNNs, via chABC treatment directly infused into the DMS, reduced grooming and digging behavior in BTBR mice. This behavior was concomitant with a strengthening of inhibitory synapses, implicating PNNs role in inhibitory plasticity in the DMS. These effects did not hold true in control mice, suggesting a preexisting condition is necessary for chABC-induced remodeling of inhibitory circuitry in the DMS that mediates the reduction of grooming and digging behaviors.