The Balance between Receptor Recycling and Trafficking toward Lysosomes Determines Synaptic Strength during Long-Term Depression
Journal of Neuroscience. 2012-09-19; 32(38): 13200-13205
DOI: 10.1523/jneurosci.0061-12.2012
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The strength of excitatory synaptic transmission depends partly on the number of
AMPA receptors (AMPARs) at the postsynaptic surface and, thus, can be modulated
by membrane trafficking events. These processes are critical for some forms of
synaptic plasticity, such as long-term potentiation and long-term depression
(LTD). In the case of LTD, AMPARs are internalized and dephosphorylated in
response to NMDA receptor activation. However, the fate of the internalized
receptors upon LTD induction and its relevance for synaptic function is still a
matter of debate. Here we examined the functional contribution of receptor
recycling versus degradation for LTD in rat hippocampal slices, and their
correlation with receptor dephosphorylation. We observed that GluA1 undergoes
sequential dephosphorylation and degradation in lysosomes after LTD induction.
However, this degradation does not have functional consequences for the
regulation of synaptic strength, and therefore, for the expression of LTD. In
contrast, the partition of internalized AMPARs between Rab7-dependent trafficking
(toward lysosomes) or Rab11-dependent endosomes (recycling back toward synapses)
is the key factor determining the extent of synaptic depression upon LTD
induction. This sorting decision is related to the phosphorylation status of
GluA1 Ser845, the dephosphorylated receptors being those preferentially targeted
for lysosomal degradation. Altogether, these new data contribute to clarify the
fate of AMPARs during LTD and emphasize the importance of membrane sorting
decisions to determine the outcome of synaptic plasticity.