The central goal is to determine whether glutamate signaling is disrupted in different striatal circuits thatunderlie repetitive behaviors in mouse models of autism. Biosensor technology will be employedconcomitantly with behavioral testing to determine real-time glutamate changes in the striatum during learning,reversal learning and marble burying. Restricted and repetitive behaviors are common to autism spectrumdisorders (ASD) but have considerable heterogeneity that can vary in severity and type. A varying severity ofcognitive impairment may arise from the degree of heightened dependence on positive reinforcement andincreased salience to unpredicted non-reinforcement. This can lead to either a learning deficit or inflexiblebehavior. Developing probabilistic learning tests for mouse models that match those used to test ASDindividuals, we have captured some of the cognitive heterogeneity reported in ASD by testing SHANK3+/- andBTBR mice. SHANK3+/- mice exhibit a probabilistic learning deficit while BTBR mice exhibit a selectiveprobabilistic reversal learning deficit. In a complementary way, we found that BTBR and SHANK3+/- miceexhibit elevated marble burying behavior, but BTBR mice have greater levels than SHANK3+/- mice. To date,there are significant gaps in our knowledge of what neural circuitry and neurochemical mechanisms are alteredthat underlie repetitive behaviors in ASD. Accumulating evidence indicates that abnormal striatal circuits mayunderlie certain repetitive behaviors. Further, a long-standing hypothesis to explain ASD features, includingcognitive deficits, is an imbalance in the brain excitation/inhibition ratio. There are different lines of evidencethat support this hypothesis, although at present, there have been no direct real-time glutamate measurementsduring behavioral expression of the symptoms. The proposed project will for the first time in two differentmouse models of ASD directly examine dynamic changes in striatal glutamate signaling during cognitive testsand expression of a stereotyped behavior. Specific Aim 1 will determine whether real-time glutamate signalingin the dorsomedial striatum, dorsolateral striatum or nucleus accumbens of SHANK3+/- and BTBR mice isaltered during spatial learning and reversal learning under conditions in which feedback is certain (100%accurate) and feedback is uncertain (80% accurate for correct choice). Specific Aim 2 will determine inSHANK3+/- and BTBR mice whether glutamate signaling differs in striatal subregions during marble buryingbehavior. Overall, examination of in vivo glutamate transmission during behavioral testing can provide a bettermechanistic understanding of ASD pathophysiology and identify novel therapeutic targets in a disorder knownto have heterogeneous symptomology.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
