ßPix heterozygous mice have defects in neuronal morphology and social interaction.

ABSTRACT

ßPix activates Rho family small GTPases, Rac1 and Cdc42 as a guanine nucleotide exchange factor. Although overexpression of ßPix in cultured neurons indicates that ßPix is involved in spine morphogenesis and synapse formation in vitro, the in vivo role of ßPix in the neuron is not well understood. Recently, we generated ßPix knockout mice that showed lethality at embryonic day 9.5. Here, we investigate the neuronal role of ßPix using ßPix heterozygous mice that are viable and fertile. ßPix heterozygous mice show decreased expression levels of ßPix proteins in various tissues including the brain. Cultured hippocampal neurons from ßPix heterozygous mice show a decrease in neurite length and complexity as well as synaptic density. Both excitatory and inhibitory synapse densities are decreased in these neurons. Golgi-staining of hippocampal tissues from the brain of these mice show reduced dendritic complexity and spine density in the hippocampal neurons. Expression levels of NMDA- and AMPA-receptor subunits and Git1 protein in hippocampal tissues are also decreased in these mice. Behaviorally, ßPix heterozygous mice exhibit impaired social interaction. Altogether, these results indicate that ßPix is required for neurite morphogenesis and synapse formation, and the reduced expression of ßPix proteins results in a defect in social behavior.