Density and function of central serotonin (5-HT) transporters, 5-HT1A and 5-HT2A receptors, and effects of their targeting on BTBR T+tf/J mouse social behavior

Abstract

J. Neurochem. (2011) 116, 291–303. Abstract BTBR mice are potentially useful tools for autism research because their behavior parallels core social interaction impairments and restricted‐repetitive behaviors. Altered regulation of central serotonin (5‐HT) neurotransmission may underlie such behavioral deficits. To test this, we compared 5‐HT transporter (SERT), 5‐HT1A and 5‐HT2A receptor densities among BTBR and C57 strains. Autoradiographic [3H] cyanoimipramine (1nM) binding to SERT was 20–30% lower throughout the adult BTBR brain as compared to C57BL/10J mice. In hippocampal membrane homogenates, [3H] citalopram maximal binding (Bmax) to SERT was 95 ± 13 fmol/mg protein in BTBR and 171 ± 20 fmol/mg protein in C57BL/6J mice, and the BTBR dissociation constant (KD) was 2.0 ± 0.3 nM versus 1.1 ± 0.2 in C57BL/6J mice. Hippocampal 5‐HT1A and 5‐HT2A receptor binding was similar among strains. However, 8‐OH‐DPAT‐stimulated [35S] GTPγS binding in the BTBR hippocampal CA1 region was 28% higher, indicating elevated 5‐HT1A capacity to activate G‐proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5‐HT1A receptor partial‐agonist, buspirone (2 mg/kg) enhanced social interactions. The D2/5‐HT2 receptor antagonist, risperidone (0.1 mg/kg) reduced marble burying, but failed to improve sociability. Overall, altered SERT and/or 5‐HT1A functionality in hippocampus could contribute to the relatively low sociability of BTBR mice.

Improvement of dizocilpine-induced social recognition deficits in mice by brexpiprazole, a novel serotonin–dopamine activity modulator

“…Previous reports demonstrated that 5-HT 1A receptor antagonists impair sociability in rodents, and that 5-HT 1A receptor agonists improved sociability in the social interaction in rodents (File and Seth, 2003;Bruins Slot et al, 2005;Snigdha and Neill, 2008;Gould et al, 2011). These findings suggest an important role of 5-HT 1A receptors in social behaviors.…”

Autoimmune Disorder and Autism

“…In the meanwhile, potential treatments for autism have been proposed based on the experimental results using BTBR mice. Two independent groups confirm the efficacy of the SERT blocker, fluoxetine for enhancement of social interactions [285,286]. Another experiment reported repetitive self-grooming behavior in the BTBR mouse model of autism was blocked by the mGluR5 antagonist Methyl-6-phenylethynylpyridine (MPEP) [287].…”

Protocadherin α (PCDHA) as a novel susceptibility gene for autism

“…[41][42][43] Recently, a de novo deletion in PCDHA13 has been observed in autism. 20 Several other members of the cadherin superfamily, such as CDH8, 44 CDH9, 45 CDH10, 45 CDH18,…”