The balance between receptor recycling and trafficking toward lysosomes determines synaptic strnght during long-term depression

Abstract

AMPA-type glutamate receptors (AMPARs) are responsible for most synaptic transmission at excitatory synapses. These receptors can be inserted or removed from synapses in response to neuronal activity, leading to long-lasting changes in synaptic strength, such as long-term potentiation or long-term depression (LTD) (Malenka and Bear, 2004). Subunit composition, phosphorylation state of AMPAR subunits, and interaction with several scaffolding proteins are important for AMPAR localization, stabilization, and membrane trafficking (Sheng and Lee, 2001; Malinow and Malenka, 2002). This complex regulation suggests highly structured dynamics in the intracellular transport of these receptors. Indeed, endosomal trafficking is important for the synaptic sorting of AMPARs, whose functional compartmentalization is governed by multiple GTPases of the Rab family (Gerges et al., 2004; Brown et al., 2005, 2007). In particular, during LTD, AMPARs are internalized by a Rab5-dependent mechanism (Brown et al., 2005). After endocytosis, AMPARs may follow two downstream pathways: recruitment to recycling endosomes for plasma membrane insertion or targeting to late endosomes en route to lysosomes for cargo degradation (Ehlers, 2000; Lin et al., 2000). However, the contribution of these alternative pathways to synaptic plasticity has not been directly evaluated. Thus, although lysosomal localization of AMPARs after LTD induction is well established (Ehlers, 2000; Lee et al., 2004), it is still unknown whether lysosomal-dependent degradation of AMPARs contributes to synaptic depression. In this work, we show that the GluA1 subunit of AMPARs is degraded in lysosomes in an NMDA receptor (NMDAR)- dependent manner upon LTD induction in hippocampal slices. This degradation occurs preferentially on dephosphorylated receptors. However, lysosomal function is not required for LTD. Instead, sorting of internalized AMPARs via Rab7-driven late endosomes favors synaptic depression, whereas Rab11-dependent receptor recycling attenuates LTD expression. Therefore, our work demonstrates that drivingAMPARtoward lysosomes is an important event for LTD as a membrane sorting decision, separable from the final enzymatic degradation of the receptor.