Tandospirone, a Partial 5-HT1A Receptor Agonist, Administered Systemically or Into Anterior Cingulate Attenuates Repetitive Behaviors in Shank3B Mice
Jeffrey T. Dunn, Jessica Mroczek, Harshkumar Patel, Michael E. Ragozzino
Abstract
BACKGROUND: Several cases of autism spectrum disorder have been linked to mutations in the SHANK3 gene. Haploinsufficiency of the SHANK3 gene contributes to Phelan-McDermid syndrome, which often presents an autism spectrum disorder phenotype along with moderate to severe intellectual disability. A SHANK3 gene deletion in mice results in elevated excitation of cortical pyramidal neurons that alters signaling to other brain areas. Serotonin 1A receptors are highly expressed on layer 2 cortical neurons and are known to have inhibitory actions. Serotonin 1A receptor agonist treatment in autistic cases with SHANK3 mutations and possibly other cases may restore excitatory and inhibitory balance that attenuates core symptoms. METHODS: A series of experiments investigated the effects of acute tandospirone treatment on spatial learning and self-grooming, subchronic treatment of tandospirone on self-grooming behavior, and the effect of tandospirone infusion into the anterior cingulate on self-grooming behavior. RESULTS: Only male Shank3B+/- mice exhibited a spatial learning deficit and elevated self-grooming. Acute i.p. injection of tandospirone, 0.01 and 0.06 mg/kg in male Shank3B+/- mice, attenuated a spatial acquisition deficit by improving sensitivity to positive reinforcement and reduced elevated self-grooming behavior. Repeated tandospirone (0.06 mg/kg) treatment attenuated elevated self-grooming behavior in male Shank3B+/- mice. Tandospirone injected into the anterior cingulate/premotor area reduced self-grooming behavior in male Shank3B+/- mice. CONCLUSIONS: These results suggest that stimulation of cortical serotonin 1A receptors may reduce repetitive behaviors and cognitive impairments as observed in autism spectrum disorder, possibly by attenuating an excitation/inhibition imbalance. Further, tandospirone may serve as a treatment in autism spectrum disorder and other disorders associated with SHANK3 mutations.