# Rem2 interacts with CaMKII at synapses and restricts long-term potentiation in hippocampus

## TL;DR

A protein called Rem2 limits the strengthening of brain connections by inhibiting another protein, CaMKII, which is important for learning and memory.

## Contribution

This study reveals a new role for Rem2 as a negative regulator of CaMKII in synaptic plasticity.

## Key findings

- Knockout of Rem2 enhances long-term potentiation (LTP) in hippocampal synapses.
- Rem2 interacts with CaMKII in dendritic spines, as shown by 2pFLIM-FRET.
- Expression of a non-inhibitory Rem2 mutant fails to rescue increased LTP in Rem2 knockout mice.

## 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 calcium/calmodulin-dependent protein kinase II (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 Rem2 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 Rem2 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 synaptic potentiation via inhibition of CaMKII activity. Further, the enhanced LTP phenotype we observe in Rem2 cKO slices reveals a previously unknown role for Rem2 in the negative regulation of CaMKII function.