Rem2 Interacts with CaMKII at Synapses and Restricts Long-term Potentiation in Hippocampus

Overview

Journal bioRxiv

Date 2024 Apr 1

PMID 38558974

Authors

Rabia Anjum

Vernon R J Clarke

Yutaro Nagasawa

Hideji Murakoshi

Suzanne Paradis

Affiliations

Soon will be listed here.

Abstract

Synaptic plasticity, the process whereby neuronal connections are either strengthened or weakened in response to stereotyped forms of stimulation, is widely believed to represent the molecular mechanism that underlies learning and memory. The holoenzyme CaMKII plays a well-established and critical role in the induction of a variety of forms of synaptic plasticity such as long-term potentiation (LTP), long-term depression (LTD) and depotentiation. Previously, we identified the GTPase Rem2 as a potent, endogenous inhibitor of CaMKII. Here, we report that knock out of enhances LTP at the Schaffer collateral to CA1 synapse in hippocampus, consistent with an inhibitory action of Rem2 on CaMKII in vivo. Further, re-expression of WT Rem2 rescues the enhanced LTP observed in slices obtained from conditional knock out (cKO) mice, while expression of a mutant Rem2 construct that is unable to inhibit CaMKII in vitro fails to rescue increased LTP. In addition, we demonstrate that CaMKII and Rem2 interact in dendritic spines using a 2pFLIM-FRET approach. Taken together, our data lead us to propose that Rem2 serves as a brake on runaway synaptic potentiation via inhibition of CaMKII activity. Further, the enhanced LTP phenotype we observe in cKO slices reveals a previously unknown role for Rem2 in the negative regulation of CaMKII function.

References

Lein E, Hawrylycz M, Ao N, Ayres M, Bensinger A, Bernard A . Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2006; 445(7124):168-76. DOI: 10.1038/nature05453. View

Flynn R, Labrie-Dion E, Bernier N, Colicos M, De Koninck P, Zamponi G . Activity-dependent subcellular cotrafficking of the small GTPase Rem2 and Ca2+/CaM-dependent protein kinase IIα. PLoS One. 2012; 7(7):e41185. PMC: 3399833. DOI: 10.1371/journal.pone.0041185. View

Stoppini L, Buchs P, Muller D . A simple method for organotypic cultures of nervous tissue. J Neurosci Methods. 1991; 37(2):173-82. DOI: 10.1016/0165-0270(91)90128-m. View

Vigil F, Mizuno K, Lucchesi W, Valls-Comamala V, Giese K . Prevention of long-term memory loss after retrieval by an endogenous CaMKII inhibitor. Sci Rep. 2017; 7(1):4040. PMC: 5481336. DOI: 10.1038/s41598-017-04355-8. View

Barria A, Malinow R . NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron. 2005; 48(2):289-301. DOI: 10.1016/j.neuron.2005.08.034. View

Tullis J, Larsen M, Rumian N, Freund R, Boxer E, Brown C . LTP induction by structural rather than enzymatic functions of CaMKII. Nature. 2023; 621(7977):146-153. PMC: 10482691. DOI: 10.1038/s41586-023-06465-y. View

Park J, Chavez A, Mineur Y, Morimoto-Tomita M, Lutzu S, Kim K . CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory. Neuron. 2016; 92(1):75-83. PMC: 5059846. DOI: 10.1016/j.neuron.2016.09.002. View

Ghiretti A, Paradis S . The GTPase Rem2 regulates synapse development and dendritic morphology. Dev Neurobiol. 2011; 71(5):374-89. PMC: 3170433. DOI: 10.1002/dneu.20868. View

Finlin B, Mosley A, Crump S, Correll R, Ozcan S, Satin J . Regulation of L-type Ca2+ channel activity and insulin secretion by the Rem2 GTPase. J Biol Chem. 2005; 280(51):41864-71. DOI: 10.1074/jbc.M414261200. View

10.

Chang B, Mukherji S, Soderling T . Characterization of a calmodulin kinase II inhibitor protein in brain. Proc Natl Acad Sci U S A. 1998; 95(18):10890-5. PMC: 27991. DOI: 10.1073/pnas.95.18.10890. View

11.

Jiao Y, Jalan-Sakrikar N, Robison A, Baucum 2nd A, Bass M, Colbran R . Characterization of a central Ca2+/calmodulin-dependent protein kinase IIalpha/beta binding domain in densin that selectively modulates glutamate receptor subunit phosphorylation. J Biol Chem. 2011; 286(28):24806-18. PMC: 3137056. DOI: 10.1074/jbc.M110.216010. View

12.

Nicoll R, Schulman H . Synaptic memory and CaMKII. Physiol Rev. 2023; 103(4):2877-2925. PMC: 10642921. DOI: 10.1152/physrev.00034.2022. View

13.

Chang J, Nakahata Y, Hayano Y, Yasuda R . Mechanisms of Ca/calmodulin-dependent kinase II activation in single dendritic spines. Nat Commun. 2019; 10(1):2784. PMC: 6592955. DOI: 10.1038/s41467-019-10694-z. View

14.

Ozden C, Sloutsky R, Mitsugi T, Santos N, Agnello E, Gaubitz C . CaMKII binds both substrates and activators at the active site. Cell Rep. 2022; 40(2):111064. PMC: 9336311. DOI: 10.1016/j.celrep.2022.111064. View

15.

Ghiretti A, Kenny K, Marr 2nd M, Paradis S . CaMKII-dependent phosphorylation of the GTPase Rem2 is required to restrict dendritic complexity. J Neurosci. 2013; 33(15):6504-15. PMC: 3666179. DOI: 10.1523/JNEUROSCI.3861-12.2013. View

16.

Strack S, Colbran R . Autophosphorylation-dependent targeting of calcium/ calmodulin-dependent protein kinase II by the NR2B subunit of the N-methyl- D-aspartate receptor. J Biol Chem. 1998; 273(33):20689-92. DOI: 10.1074/jbc.273.33.20689. View

17.

Herring B, Nicoll R . Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP. Proc Natl Acad Sci U S A. 2016; 113(8):2264-9. PMC: 4776457. DOI: 10.1073/pnas.1600179113. View

18.

Royer L, Herzog J, Kenny K, Tzvetkova B, Cochrane J, Marr 2nd M . The Ras-like GTPase Rem2 is a potent inhibitor of calcium/calmodulin-dependent kinase II activity. J Biol Chem. 2018; 293(38):14798-14811. PMC: 6153278. DOI: 10.1074/jbc.RA118.003560. View

19.

Stiegler A, Boggon T . The pseudoGTPase group of pseudoenzymes. FEBS J. 2020; 287(19):4232-4245. PMC: 7544640. DOI: 10.1111/febs.15554. View

20.

Xie Z, Srivastava D, Photowala H, Kai L, Cahill M, Woolfrey K . Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron. 2007; 56(4):640-56. PMC: 2118058. DOI: 10.1016/j.neuron.2007.10.005. View