title: GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors.
abstract: Learning depends on experience-dependent modification of synaptic efficacy and neuronal connectivity in the brain. We provide direct evidence for physiological roles of the recycling endosome protein GRASP1 in glutamatergic synapse function and animal behavior. Mice lacking GRASP1 showed abnormal excitatory synapse number, synaptic plasticity, and hippocampal-dependent learning and memory due to a failure in learning-induced synaptic AMPAR incorporation. We identified two GRASP1 point mutations from intellectual disability (ID) patients that showed convergent disruptive effects on AMPAR recycling and glutamate uncaging-induced structural and functional plasticity. Wild-type GRASP1, but not ID mutants, rescued spine loss in hippocampal CA1 neurons in Grasp1 knockout mice. Together, these results demonstrate a requirement for normal recycling endosome function in AMPAR-dependent synaptic function and neuronal connectivity in vivo, and suggest a potential role for GRASP1 in the pathophysiology of human cognitive disorders.
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Chiu
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Graham Hugh
authors.initials: GH
authors.lastname: Diering
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Ye
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, University of Miyazaki, Miyazaki 889-1601, Japan.
authors.forename: Kogo
authors.initials: K
authors.lastname: Takamiya
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Yuwu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Tejasvi
authors.initials: T
authors.lastname: Niranjan
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: rhuganir@jhmi.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism*; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D007858:Learning / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009473:Neuronal Plasticity / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism* / Q000502:physiology; D013569:Synapses / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C000622903:GRASP-1 protein, mouse; C485827:GRIPAP1 protein, human; D018091:Receptors, AMPA; D018698:Glutamic Acid
keywords: GRIP1; glutamate receptor; glutamate uncaging; intellectual disability; long-term potentiation; neurodevelopmental disorder; neuronal connectivity; recycling endosomes; structural plasticity; syntaxin13