The Balance between Receptor Recycling and Trafficking toward Lysosomes Determines Synaptic Strength during Long-Term Depression
The Balance between Receptor Recycling and Trafficking toward Lysosomes Determines Synaptic Strength during Long-Term Depression
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DOI：
10.1523/jneurosci.0061-12.2012
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发表时间：
2012-09-19
影响因子：
5.3
通讯作者：
Esteban, Jose A.
中科院分区：
文献类型：
--
作者：
Fernandez-Monreal, Monica;Brown, Tyler C.;Esteban, Jose A.
兴奋性突触传递的强度部分取决于突触后表面AMPA受体（AMPAR）的数量，因此可以通过膜运输事件进行调节。这些过程对于某些形式的突触可塑性至关重要，例如长时程增强和长时程抑制（LTD）。在LTD的情况下，AMPAR响应于NMDA受体活化而内化和去磷酸化。然而，LTD诱导后内化受体的命运及其与突触功能的相关性仍然是一个有争议的问题。在这里，我们研究了受体回收与降解LTD在大鼠海马脑片的功能贡献，以及它们与受体去磷酸化的相关性。我们观察到，GluA1在LTD诱导后在溶酶体中经历顺序的去磷酸化和降解。然而，这种退化并没有功能的后果，突触强度的调节，因此，为LTD的表达。相比之下，Rab7依赖的贩运（向溶酶体）或Rab11依赖的内体（回收回突触）之间的分区内化AMPAR是决定LTD诱导后突触抑制程度的关键因素。这种分选决定与GluA1 Ser845的磷酸化状态有关，去磷酸化的受体是那些优先靶向溶酶体降解的受体。总之，这些新的数据有助于阐明LTD期间AMPAR的命运，并强调膜分选决定对确定突触可塑性结果的重要性。
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.