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MTMR2 is a 3-phosphatase specific for the phosphoinositides PI(3)P and PI(3,5)P(2), which are mainly present on endosomes. Mutations in the MTMR2 gene in Schwann cells lead to a severe demyelinating peripheral neuropathy known as Charcot-Marie-Tooth disease type 4B1. MTMR2 expression is also detected in peripheral and central neurons, but neural functions of MTMR2 remain unclear. Here, we report that MTMR2 is localized to excitatory synapses of central neurons via direct interaction with PSD-95, a postsynaptic scaffolding protein abundant at excitatory synapses. Knockdown of MTMR2 in cultured neurons markedly reduces excitatory synapse density and function. This effect is rescued by wild-type MTMR2 but not by a mutant MTMR2 lacking PSD-95 binding or 3-phosphatase activity. MTMR2 knockdown leads to a decrease in the intensity of EEA1-positive early endosomes in dendrites but increases the intensity in the cell body region. Moreover, MTMR2 suppression promotes endocytosis, but not recycling, of the GluR2 subunit of AMPA receptors, which is an endosomal cargo. In addition, colocalization of internalized GluR2 with Lamp1-positive late endosomes/lysosomes is enhanced in the cell body area but not in dendrites. These results suggest that PSD-95-interacting MTMR2 contributes to the maintenance of excitatory synapses by inhibiting excessive endosome formation and destructive endosomal traffic to lysosomes.

The Phosphoinositide 3-Phosphatase MTMR2 Interacts with PSD-95 and Maintains Excitatory Synapses by Modulating Endosomal Traffic