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Neuron. 2016 Oct 5;92(1):75-83. doi: 10.1016/j.neuron.2016.09.002. Epub 2016 Sep 22.

CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory.

Author information

  • 1Department of Cellular and Molecular Physiology, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 2Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2340000, Chile.
  • 3Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 4Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 5Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: pablo.castillo@einstein.yu.edu.
  • 6Department of Cellular and Molecular Physiology, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: susumu.tomita@yale.edu.

Abstract

Protein phosphorylation is an essential step for the expression of long-term potentiation (LTP), a long-lasting, activity-dependent strengthening of synaptic transmission widely regarded as a cellular mechanism underlying learning and memory. At the core of LTP is the synaptic insertion of AMPA receptors (AMPARs) triggered by the NMDA receptor-dependent activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). However, the CaMKII substrate that increases AMPAR-mediated transmission during LTP remains elusive. Here, we identify the hippocampus-enriched TARPγ-8, but not TARPγ-2/3/4, as a critical CaMKII substrate for LTP. We found that LTP induction increases TARPγ-8 phosphorylation, and that CaMKII-dependent enhancement of AMPAR-mediated transmission requires CaMKII phosphorylation sites of TARPγ-8. Moreover, LTP and memory formation, but not basal transmission, are significantly impaired in mice lacking CaMKII phosphorylation sites of TARPγ-8. Together, these findings demonstrate that TARPγ-8 is a crucial mediator of CaMKII-dependent LTP and therefore a molecular target that controls synaptic plasticity and associated cognitive functions.

PMID:
27667007
PMCID:
PMC5059846
[Available on 2017-10-05]
DOI:
10.1016/j.neuron.2016.09.002
[PubMed - in process]
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