5HT2A Receptor Antagonist Treatment for Repetitive Behaviors and Restricted Interests in BTBR Mice

Individuals with autism spectrum disorder (ASD) commonly exhibit an “insistence on sameness” which is characterized by a compulsive adherence to a thought pattern or stereotyped behavior. Insistence on sameness in ASD can result in behavioral flexibility deficits when a situation requires a shift in thought patterns or actions. To date, there lacks effective treatments to alleviate insistence on sameness features, which is in part due to the limited knowledge about the underlying neuropathophysiology contributing to behavioral inflexibility and stereotyped behavior. This project investigated whether pharmacologically targeting 5HT2A receptors in an idiopathic model of ASD, the BTBR mouse, affects the expression of a phenotype that is related to RRBs in ASD. The findings suggest that altered 5HT2A receptor signaling in BTBR mice may contribute to behavioral flexibility deficits and elevated grooming which can be attenuated by systemic treatment with a 5HT2A receptor antagonist. A behavioral flexibility deficit observed in BTBR mice may result, in part, from increased 5HT2A receptor signaling in the dorsomedial striatum. In contrast, 5HT2A receptor signaling in the orbitofrontal cortex may be normal in BTBR mice, but when 5HT2A receptor blockade of this region leads to perseveration of both cognitive and stereotyped behaviors. Overall, these findings suggest that 5HT2A receptor antagonist treatment may be effective in ameliorating RRBs in ASD, in part, by correcting altered 5HT2A receptor signaling in the striatum

Oxotremorine treatment reduces repetitive behaviors in BTBR T+ tf/J mice

Repetitive behaviors with restricted interests is one of the core criteria for the diagnosis of autism spectrum disorder (ASD). Current pharmacotherapies that target the dopaminergic or serotonergic systems have limited effectiveness in treating repetitive behaviors. Previous research has demonstrated that administration of muscarinic cholinergic receptor (mAChR) antagonists can exacerbate motor stereotypies while mAChR agonists reduce stereotypies. The present study determined whether the mAChR agonist, oxotremorine affected repetitive behaviors in the BTBR T+ tf/J (BTBR) mouse model of autism. To test the effects of oxotremorine on repetitive behaviors, marble burying and grooming behavior were measured in BTBR mice and compared to that in C57BL/6J (B6) mice. The effects of oxotremorine on locomotor activity was also measured. Thirty minutes before each test, mice received an intraperitoneal injection of saline, 0.001mg or 0.01mg of oxotremorine methiodide. Saline treated BTBR mice exhibited increased marble burying and self-grooming behavior compared to that of saline-treated B6 mice. Oxotremorine significantly reduced marble burying and self48 grooming behavior in BTBR mice, but had no significant effect in B6 mice. In addition, oxotremorine did not affect locomotor activity in BTBR mice, but significantly reduced locomotor activity in B6 mice at the 0.01mg dose. These findings demonstrate that activation of mAChRs reduces repetitive behavior in the BTBR mouse and suggest that treatment with a mAChR agonist may be effective in reducing repetitive behaviors in ASD

Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex.

BACKGROUND:Epidemiological studies suggest that the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia is increased by prenatal exposure to viral or bacterial infection during pregnancy. It is still unclear how activation of the maternal immune response interacts with underlying genetic factors to influence observed ASD phenotypes. METHODS:The current study investigated how maternal immune activation (MIA) in mice impacts gene expression in the frontal cortex in adulthood, and how these molecular changes relate to deficits in cognitive flexibility and social behavior, and increases in repetitive behavior that are prevalent in ASD. Poly(I:C) (20 mg/kg) was administered to dams on E12.5 and offspring were tested for social approach behavior, repetitive grooming, and probabilistic reversal learning in adulthood (n = 8 vehicle; n = 9 Poly(I:C)). We employed next-generation high-throughput mRNA sequencing (RNA-seq) to comprehensively investigate the transcriptome profile in frontal cortex of adult offspring of Poly(I:C)-exposed dams. RESULTS:Exposure to poly(I:C) during gestation impaired probabilistic reversal learning and decreased social approach in MIA offspring compared to controls. We found long-term effects of MIA on expression of 24 genes, including genes involved in glutamatergic neurotransmission, mTOR signaling and potassium ion channel activity. Correlations between gene expression and specific behavioral measures provided insight into genes that may be responsible for ASD-like behavioral alterations. CONCLUSIONS:These findings suggest that MIA can lead to impairments in cognitive flexibility in mice similar to those exhibited in ASD individuals, and that these impairments are associated with altered gene expression in frontal cortex