CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory.
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.
Department 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.
Joongkyu
J
Park
Dominick 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.
Andrés E
AE
Chávez
Kavli 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.
Yann S
YS
Mineur
Department 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.
Megumi
M
Morimoto-Tomita
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Stefano
S
Lutzu
Department 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.
Kwang S
KS
Kim
Kavli 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.
Marina R
MR
Picciotto
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: pablo.castillo@einstein.yu.edu.
Pablo E
PE
Castillo
Department 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.
Susumu
S
Tomita
D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism
D015220:Calcium Channels; D018091:Receptors, AMPA; C515550:TARP gamma-8 protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
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