SHRM4, A PROTEIN INVOLVED IN X-LID, DRIVES GABA B RECEPTORS INTO DENDRITES THROUGH ITS ASSOCIATION WITH THE DYNEIN/DYNACTIN COMPLEX

Mutations in the KIAA1202 gene coding for the Shrm4 protein have been involved in intellectual disabilities (ID). However, its expression and role in the brain is still unknown. Our data revealed that Shrm4 is present in both cortical and hippocampal primary cultured neurons and localizes at the pre- and post-synapse. ShRNA-mediated Shrm4 knock-down leads to a dramatic reduction in spine density and length. Furthermore, we detected a significant decrease in the expression level of synaptic markers compared to scrambled control. Using different biochemical and imaging approaches, we showed that the N-terminal PDZ domain of Shrm4 interacts directly with the C-terminal tail of GABAB receptor subunit isoforms 1 (GABAB1) (both GABAB1a and GABAB1b subunits). We observed for the first time that Shrm4 regulates GABABRs transport in dendrites by modulating its association with the microtubule-dependent dynein/dynactin motor complex. According to our hypothesis, in vivo and in vitro Shrm4 knockdown reduces GABAB receptor-mediated K+ currents induced by baclofen application. These results supported the presence of a trimeric complex, necessary for the correct targeting of GABAB receptors to dendrites and for its physiological role in brain transmission. These observations raised evidences that symptoms observed in Shrm4 deficient human patients such as epilectic seizures could arise from reduced level of functional GABAB receptors.