Serotonin 5-HT receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin transporter Ala56 variant.

Rationale: Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969.

Objectives: We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT receptor binding and 5-HT-mediated sensorimotor deficits.

Methods: Specific binding to 5-HT receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined.

Results: While enhanced SERT function increased 5-HT receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum.

Conclusions: While reducing 5-HT receptors may attenuate sensorimotor gating deficits, increased 5-HT levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.