title: The balance between receptor recycling and trafficking toward lysosomes determines synaptic strength during long-term depression.
abstract: 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.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Fernández-Monreal
authors.forename: Tyler C
authors.initials: TC
authors.lastname: Brown
authors.forename: María
authors.initials: M
authors.lastname: Royo
authors.forename: José A
authors.initials: JA
authors.lastname: Esteban
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D029681:Arabidopsis Proteins / Q000235:genetics / Q000378:metabolism; D001703:Biophysics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D007976:Leupeptins / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000648:ultrastructure*; D009924:Organ Culture Techniques; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013569:Synapses / Q000502:physiology*; D014162:Transfection / Q000379:methods
chemical_list: D029681:Arabidopsis Proteins; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C417970:FIP2 protein, Arabidopsis; D007976:Leupeptins; D018091:Receptors, AMPA; C492252:Wdr44 protein, rat; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D019204:GTP-Binding Proteins; C032854:leupeptin