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Neuron. 2017 Mar 22;93(6):1405-1419.e8. doi: 10.1016/j.neuron.2017.02.031. Epub 2017 Mar 9.

GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors.

Author information

1
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
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.
3
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, University of Miyazaki, Miyazaki 889-1601, Japan.
4
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
5
Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
6
Greenwood Genetic Center, Greenwood, SC 29646, USA.
7
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: rhuganir@jhmi.edu.

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.

KEYWORDS:

GRIP1; glutamate receptor; glutamate uncaging; intellectual disability; long-term potentiation; neurodevelopmental disorder; neuronal connectivity; recycling endosomes; structural plasticity; syntaxin13

PMID:
28285821
PMCID:
PMC5382714
DOI:
10.1016/j.neuron.2017.02.031
[Indexed for MEDLINE]
Free PMC Article

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