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


Address correspondence and reprint requests to Georgianna G. Gould, PhD, Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA. E-mail:


J. Neurochem. (2011) 116, 291–303.


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.