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‐HT_1A and 5‐HT_2A 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 (B_max) 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 (K_D) was 2.0 ± 0.3 nM versus 1.1 ± 0.2 in C57BL/6J mice. Hippocampal 5‐HT_1A and 5‐HT_2A 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‐HT_1A capacity to activate G‐proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5‐HT_1A 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‐HT_1A functionality in hippocampus could contribute to the relatively low sociability of BTBR mice.