Regulation of dendritic structure and synaptic plasticity by TANC, BCR and ABR

Abstract

The small GTPase Rac1 positively regulates dendritic spine morphogenesis. Little is known, however, about how Rac1 is regulated and whether Rac1 regulates synaptic plasticity. We found that BCR and ABR, two closely related Rac GTPase-activating proteins, directly interact with PSD-95, an abundant postsynaptic scaffolding protein. BCR-/- and ABR-/- mice show enhanced basal Rac1 activity and increased spine density. They also exhibit reduced long-term potentiation (LTP) and impaired learning and memory. Importantly, LTP in wild-type mice requires active Rac1, whereas LTP in BCR-/- and ABR-/- mice is completely resistant to Rac1 inhibition. This unexpected result is consistent with the idea that enhanced basal Rac1 activity in BCR-/- and ABR-/- mice induces compensatory inhibition of Rac1 activation during LTP. Collectively, these results implicate BCR and ABR in negatively regulating Rac1, dendritic spines, and LTP, and suggest the existence of two interchangeable modes of LTP distinguished by their distinctive requirements for Rac1. In addition, we identified that a novel family of postsynaptic density (PSD) proteins termed TANC that directly interacts with PSD-95. The two isoforms in the TANC family (TANC1 and TANC2) contain various domains including eleven ankyrin repeats, three tetratricopeptide repeats (TPR), a coiled coil, and a C-terminal PDZ domain-binding motif that binds to the PDZ domains of PSD-95. Both TANC isoforms are brain specific and enriched in PSD fractions, but their mRNAs are distinctly distributed in various brain regions. TANC forms a complex with PSD-95 both in vitro and in vivo. TANC requires PSD-95 interaction for its synaptic localization. Importantly, overexpression of TANC1 in cultured neurons promotes dendritic spine and knockdown of siRNA decreases the spine density, but not width and length of spines. To further examine in vivo function of TANC proteins, we generated TANC1 and TANC2 knock-out mice. TANC1-deficient mice show nor...