title: The Retromer Supports AMPA Receptor Trafficking During LTP.
abstract: Alterations in the function of the retromer, a multisubunit protein complex that plays a specialized role in endosomal sorting, have been linked to Alzheimer's and Parkinson's diseases, yet little is known about the retromer's role in the mature brain. Using in vivo knockdown of the critical retromer component VPS35, we demonstrate a specific role for this endosomal sorting complex in the trafficking of AMPA receptors during NMDA-receptor-dependent LTP at mature hippocampal synapses. The impairment of LTP due to VPS35 knockdown was mechanistically independent of any role of the retromer in the production of Aβ from APP. Finally, we find surprising differences between Alzheimer's- and Parkinson's-disease-linked VPS35 mutations in supporting this pathway. These findings demonstrate a key role for the retromer in LTP and provide insights into how retromer malfunction in the mature brain may contribute to symptoms of common neurodegenerative diseases. VIDEO ABSTRACT.
authors.affiliation: Nancy Pritzker Laboratory, Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5453, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Temkin
authors.affiliation: Nancy Pritzker Laboratory, Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5453, USA.
authors.forename: Wade
authors.initials: W
authors.lastname: Morishita
authors.affiliation: Nancy Pritzker Laboratory, Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5453, USA.
authors.forename: Debanjan
authors.initials: D
authors.lastname: Goswami
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5453, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Arendt
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5453, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Nancy Pritzker Laboratory, Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5453, USA. Electronic address: malenka@stanford.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Malenka
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics*; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D056827:Endosomal Sorting Complexes Required for Transport; D018091:Receptors, AMPA; D033921:Vesicular Transport Proteins; C101274:Vps35 protein, mouse
keywords: Alzheimer’s disease; Parkinson’s disease; amyloid beta (Aβ); long-term potentiation (LTP); retromer; synaptic plasticity