TY - JOUR
T1 - CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory
AU - Park, Joongkyu
AU - Chávez, Andrés E.
AU - Mineur, Yann S.
AU - Morimoto-Tomita, Megumi
AU - Lutzu, Stefano
AU - Kim, Kwang S.
AU - Picciotto, Marina R.
AU - Castillo, Pablo E.
AU - Tomita, Susumu
N1 - Funding Information:
The authors thank the members of the S.T. lab and the P.E.C. Lab for helpful discussions, the NIDA center core (P30DA018343), and the Yale Keck facility for analysis of phosphorylation sites and peptide synthesis and Millipore for generating antibodies. We thank Roger Nicoll and David Bredt for providing the TARPγ-3/4/8 KO mice, the Yale transgenic facility for assistance with mice, and the UC Davis/NeuroMab facility (NIH U24NS050606) for antibodies. This work is supported by the Kavli Institute (S.T.) and NIH grants MH077939 (S.T.), MH081935 and DA017392 (P.E.C.), DA14241 and MH77681 (M.R.P.), and MH105824 (Y.S.M.). This work was also supported by the Fostering Next-Generation Researchers Program type II (2012R1A6A3A03039314 to J.P.) funded by the National Research Foundation of Korea (NRF). A.E.C was partially supported by a National Alliance for Research on Schizophrenia and Depression Young Investigator Grant from the Brain & Behavior Research Foundation and by the Millennium Nucleus Nu-MIND (NC 130011) and the Millennium Institute CINV (P09-022F).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/10/5
Y1 - 2016/10/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2016.09.002
DO - 10.1016/j.neuron.2016.09.002
M3 - Article
C2 - 27667007
AN - SCOPUS:84992688642
SN - 0896-6273
VL - 92
SP - 75
EP - 83
JO - Neuron
JF - Neuron
IS - 1
ER -