Effects of 5-HT1A Receptor Agonism on Repetitive Grooming and Learning Behavior in Shank3B Mice
thesisposted on 27.07.2018, 00:00 by Jeffrey T Dunn
Restricted interests and repetitive behaviors (RRBs) represent a core diagnostic category of autism spectrum disorder (ASD). RRBs encompass a range of behaviors from motor stereotypy to cognitive rigidity. Several cases of ASD have been linked to deletion or mutation in the SHANK3 gene. Haploinsufficiency of the SHANK3 gene contributes to Phelan-McDermid syndrome (PMS), a neurodevelopmental disorder which often presents an ASD behavioral phenotype and moderate to severe intellectual disability. Deletion of the SHANK3 gene in mice results in elevated excitation of cortical pyramidal neurons that alters output to other cortical and subcortical areas. Serotonin 1A receptors (5-HT1ARs) are highly expressed on layer 2 cortical neurons and are known to have inhibitory actions. Treatment with a 5-HT1AR agonist in PMS may restore excitatory and inhibitory balance to cortico-basal ganglia-thalamo-cortical circuits that alleviate RRBs and learning deficits. To begin exploring this possibility, the present experiments determined whether acute treatment with the partial 5-HT1AR agonist, tandospirone in Shank3B+/- mice attenuated elevated self-grooming and a probabilistic learning deficit. Systemic treatment with tandospirone, 0.01 and 0.06 mg/kg doses, attenuated elevated self-grooming behavior in Shank3B+/- mice without affecting locomotor and rearing behavior. Tandospirone, at 0.06 mg/kg, alleviated a learning impairment in Shank3B+/- mice on a spatial discrimination task using 80/20 probabilistic reinforcement. Together, these results indicate the potential for tandospirone as a treatment for behavioral symptoms characteristic of PMS and ASD.