A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function.

ABSTRACT: MINT2/APBA2 is a synaptic adaptor protein involved in excitatory synaptic transmission. Several nonsynonymous coding variants in MINT2 have been identified in autism spectrum disorders (ASDs); however, these rare variants have not been examined functionally and the pathogenic mechanisms are unknown. Here, we examined the synaptic effects of rat Mint2 N723S mutation (equivalent to autism-linked human MINT2 N722S mutation) which targets a conserved asparagine residue in the second PDZ domain of Mint2 that binds to neurexin-1? (Nrxn1?), a presynaptic cell-adhesion protein implicated in ASDs. We show the N723S mutation impairs Nrxn1? stabilization and trafficking to the membrane while binding to Nrxn1? remains unaffected. Using time-lapse imaging in primary mouse neurons, we found that the N723S mutant had more immobile puncta at neuronal processes compared to Mint2 wild type. We therefore, reasoned that the N723S mutant may alter the co-transport of Nrxn1? at axonal processes to presynaptic terminals. Indeed, we found the N723S mutation affected Nrxn1? localization at presynaptic terminals which correlated with a decrease in Nrxn-mediated synaptogenesis and miniature event frequency in excitatory synapses. Together, our data reveal Mint2 N723S leads to neuronal dysfunction, in part due to alterations in Nrxn1? surface trafficking and synaptic function of Mint2.

SUBMITTER: Lin AY 

PROVIDER: S-EPMC6465354 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature