Density and function of central serotonin (5-HT) transporters, 5-HT _1A and 5-HT_2A receptors, and effects of their targeting on BTBR T+tf/J mouse social behavior

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-HT ₂ 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.