Disruption of the endocytic protein HIP1 results in neurological deficits and decreased AMPA receptor trafficking

Martina Metzler, Bo Li, Lu Gan, John Georgiou, Claire Anne Gutekunst, Yushan Wang, Enrique Torre, Rebecca S. Devon, Rosemary Oh, Valerie Legendre-Guillemin, Mark Rich, Christine Alvarez, Marina Gertsenstein, Peter S. McPhersons, Andras Nagy, Yu Tian Wang, John C. Roder, Lynn A. Raymond, Michael R. Hayden

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Huntingtin interacting protein 1 (HIP1) is a recently identified component of clathrin-coated vesicles that plays a role in clathrin-mediated endocytosis. To explore the normal function of HIP1 in vivo, we created mice with targeted mutation in the HIP1 gene (HIP1-/-). HIP1-/- mice develop a neurological phenotype by 3 months of age manifest with a failure to thrive, tremor and a gait ataxia secondary to a rigid thoracolumbar kyphosis accompanied by decreased assembly of endocytic protein complexes on liposomal membranes. In primary hippocampal neurons, HIP1 colocalizes with GluR1-containing AMPA receptors and becomes concentrated in cell bodies following AMPA stimulation. Moreover, a profound dose-dependent defect in clathrin-mediated internalization of GluR1-containing AMPA receptors was observed in neurons from HIP1-/- mice. Together, these data provide strong evidence that HIP1 regulates AMPA receptor trafficking in the central nervous system through its function in clathrin-mediated endocytosis.

Original languageEnglish
Pages (from-to)3254-3266
Number of pages13
JournalThe EMBO Journal
Issue number13
Publication statusPublished - 1 Jul 2003
Externally publishedYes


  • Clathrin
  • Endocytosis
  • Glutamate receptors
  • Huntington's disease
  • Synapse

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