A Dual Role for LAR-RPTP in Regulating Long-distance Transport and Synaptic Retention of AMPARs, Essential for Long Term Associative Memory

Abstract

The AMPA subtype of ionotropic glutamate receptors (AMPARs) plays an essential role in excitatory synaptic transmission, learning, and memory. The majority of AMPARs are made in the cell body and are transported by molecular motors to synapses. Maintaining the proper number of synaptic receptors requires coordinated regulation of receptor production, export from the soma and delivery at synapses. This major logistical process is essential for circuit function and behavior. Although recent studies have shown that long-distance synaptic transport is regulated by neuronal activity, little is known about the mechanisms that coordinate somatic export or synaptic delivery and removal. Here we show that loss of the PTP-3A isoform of the receptor tyrosine phosphatase PTP-3 (the C. elegans homologue of vertebrate LAR-RPTP) leads to a [~]60% decrease in AMPAR transport; this affects synaptic delivery of AMPARs and synaptic functions necessary for long-term associative olfactory memory in C. elegans. Interestingly, while complete loss of PTP-3A leads to defects in transport and local synaptic trafficking of AMPARs, loss of only PTP-3 phosphatase function affects local synaptic recycling and retention of AMPARs. Finally, we show that the N-terminus of PTP-3A regulates transport, whereas the C-terminal regulates synaptic retention of AMPARs. Altogether, our results suggest a model in which the two domains of PTP-3/LAR-RPTPs have specific, complementary roles in coordinating somatic export and local retention of AMPARs essential for long-term associative memory.