Roles Of EPAC And MEA6 In The Cerebellar Physiological Function

Different forms of plasticity in Purkinje cells(PCs)are critical to motor learning and cerebellum-related disorders.Cyclic adenosine monophosphate(cAMP)plays a central role in presynaptic long-term potentiation(LTP)at cerebellar and hippocampal synapses.However,its downstream machinery involved in presynaptic LTP has been unclear.Here,we investigated the roles of EPAC,the cAMP effector,in 8-Hz stimulation-induced presynaptic LTP at parallel fiber(PF)-PC synapses.We demonstrated that EPAC activation induced PKCs activation and threonine phosphorylation of RIMla,which further facilitates the assembly of Rab3A-RIM1?-Munc13-1 tripartite complex and the docking of synaptic vesicles at active zones.The deletion of EPAC 1 and EPAC2 did not affect the cyto-architecture of the cerebellum,but both 8-Hz LTP and forskolin-mediated potentiation of PF neurotransmission were impaired,demonstrating that EPAC contributes to cAMP-dependent potentiation of transmitter release and presynaptic LTP.Our work highlights that the EPAC-PKC? module may participate in presynaptic plasticity at not only PF-PC synapses,but also many other synapses,considering the rich expression of EPAC and PKC? at presynaptic sites in the CNS.It is reported that MEA6(P521A)gene mutation might be related to Fahr's syndrome,which comprises neurological,movement,and neuropsychiatric disorders.Meningioma expressed antigen 6(MEA6)is located in endoplasmic reticulum(ER)exit sites and regulates the transport of collagen,very low density lipoprotein,and insulin.Here,we show that MEA6 is critical to cerebellar development and motor performance.Mice with conditional knockout of MEA6(Nestin-Cre;MEA6F/F)display smaller sizes of body and brain compared to control animals,and survive maximal 28 days after birth.Immunohistochemical and behavioral studies demonstrate that these mutant mice have defects in cerebellar development and motor performance.In contrast,PC deletion of MEA6(pCP2-Cre;MEA6F/F)causes milder phenotypes in cerebellar morphology and motor behaviors.While pCP2-Cre;MEA6F/F mice have normal lobular formation and gait,they present the extensive self-crossing of PC dendrites and damaged motor learning.Interestingly,the expression of key molecules that participates in cerebellar development,including Slit2 and brain derived neurotrophic factor(BDNF),is significantly increased in ER,suggesting that MEA6 ablation impairs ER function and thus these proteins are arrested in ER.Our study provides insight into the roles of MEA6 in the brain and the pathogenesis of Fahr' s syndrome.