Prenatal stress and fluoxetine exposure in mice differentially affect repetitive behaviors and synaptic plasticity in adult male and female offspring.

Autism spectrum disorder (ASD) is characterized by social communication impairments with restricted and repetitive behaviors (RRBs). The increase in prevalence of ASD and the heterogeneity of symptom severity may arise from a complex interaction of environmental and genetic factors that alter synaptic plasticity. Maternal stress during pregnancy, which is linked to depression, may be one risk factor for an ASD phenotype in offspring. Selective serotonin reuptake inhibitor (SSRI) treatment can be effective in alleviating maternal depression but prenatal SSRI exposure itself may be a risk factor for autism in offspring. The present study investigated in C57BL/6J pregnant mice whether restraint stress (G4-18) and/or treatment with the SSRI fluoxetine (G8-18) affects autism-related behaviors and hippocampal synaptic plasticity in male and female offspring. The findings indicate that restraint stress reduces preference for sucrose reward in pregnant dams that is reversed by fluoxetine. In adult male offspring, combined prenatal stress and SSRI exposure increased self-grooming and impaired spatial reversal learning. In adult female offspring, the prenatal experiences did not affect self-grooming, but restraint stress alone or SSRI exposure alone impaired spatial reversal learning. Prenatal stress reduced anxiety-related behavior in male and female offspring. Further, LTP induced by theta-burst stimulation of Schaffer-commissural afferents in field CA1 was significantly reduced in female offspring exposed to prenatal stress alone or combination with fluoxetine. Together, these findings suggest that exposure to prenatal stress, SSRI treatment or the combination differentially affects male and female offspring in autism-like behaviors and synaptic plasticity.

Tandospirone, a Partial 5-HT1A Receptor Agonist, Administered Systemically or Into Anterior Cingulate Attenuates Repetitive Behaviors in Shank3B Mice.

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.