Bisecting GlcNAc in N-glycan regulates synaptic maturation

Bisecting GlcNAc, a central branch in N-glycans synthesized by the N-acetylglucosaminyltransferase III (MGAT3; also known as GnT-III), is highly expressed in neurons. Although pathological roles of MGAT3 and bisecting GlcNAc have been demonstrated in Alzheimer's disease, their physiological functions in neurons remain unclear. To identify their physiological functions, here we examine the morphology of neurons in knockout (Mgat3-/-) mouse brains and investigate the expression and localization of bisecting GlcNAc-bearing glycoproteins involved in neuronal activity and morphogenesis. We found impaired neurite extension and spine maturation in cultured cortical neurons of Mgat3-/- mice, along with reduced stimulus-induced in vivo neuronal activity. Moreover, key glycoproteins for these processes (specifically α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA]-type glutamate receptors) showed reduced accumulation in postsynaptic density membrane fractions and a weakened interaction with transmembrane AMPA receptor regulatory protein 8 (TARP8) in Mgat3-/- mouse brain. These results suggest that bisecting GlcNAc plays important roles in synaptic maturation, highlighting a new mechanism for neuronal activity regulated by specific N-glycans.