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

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


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.

MeSH terms

  • Animals
  • Avoidance Learning / physiology
  • CA1 Region, Hippocampal / physiology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Case-Control Studies
  • Cells, Cultured
  • Endosomes / metabolism*
  • Glutamic Acid / physiology
  • Humans
  • Intellectual Disability / genetics
  • Learning / physiology*
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Knockout
  • Mutation
  • Neuronal Plasticity / physiology*
  • Receptors, AMPA / metabolism*
  • Receptors, AMPA / physiology
  • Synapses / physiology


  • Carrier Proteins
  • GRASP-1 protein, mouse
  • GRIPAP1 protein, human
  • Receptors, AMPA
  • Glutamic Acid