Loss of Ryanodine Receptor 2 impairs neuronal activity-dependent remodeling of dendritic spines and triggers compensatory neuronal hyperexcitability

Fabio Bertan,Dennis Dalügge,Pierluigi Nicotera,Fabrizio Gardoni,Manuel Mittag,Daniele Bano,Alessandra Fornarelli,Liudmila Sosulina,Stefan Remy,Martin Fuhrmann,Monica Di Luca,Elena Marcello,Lena Wischhof

doi:10.1038/s41418-020-0584-2

Abstract

Dendritic spines are postsynaptic domains that shape structural and functional properties of neurons. Upon neuronal activity, Ca2+ transients trigger signaling cascades that determine the plastic remodeling of dendritic spines, which modulate learning and memory. Here, we study in mice the role of the intracellular Ca2+ channel Ryanodine Receptor 2 (RyR2) in synaptic plasticity and memory formation. We demonstrate that loss of RyR2 in pyramidal neurons of the hippocampus impairs maintenance and activity-evoked structural plasticity of dendritic spines during memory acquisition. Furthermore, post-developmental deletion of RyR2 causes loss of excitatory synapses, dendritic sparsification, overcompensatory excitability, network hyperactivity and disruption of spatially tuned place cells. Altogether, our data underpin RyR2 as a link between spine remodeling, circuitry dysfunction and memory acquisition, which closely resemble pathological mechanisms observed in neurodegenerative disorders.

Highlights

Spine number and structural plasticity determine the information storage underlying learning and memory processesThese authors contributed : Fabio Bertan, Lena Wischhof, Liudmila Sosulina, Manuel MittagThese authors jointly supervised this work: Martin Fuhrmann, Stefan Remy, Daniele Bano, and Pierluigi NicoteraEdited by G
We found that Synapsin-Cretg/wt;Ryr2fl/fl mice exhibited reduced spine density in the hippocampus compared to control littermates
We demonstrated that Ryanodine Receptor 2 (RyR2) regulates spine number, synaptic connectivity and activity-dependent structural plasticity associated with hippocampal memory processes in adult brain

Summary

Introduction

These authors contributed : Fabio Bertan, Lena Wischhof, Liudmila Sosulina, Manuel Mittag. We investigated in vitro, ex vivo and in vivo the specific function of RyR2 in the maintenance and activitydependent structural plasticity of dendritic spines in the post-developmental brain Our models using both transgenic and AAV-mediated deletion enabled us to investigate the role of RyR2 in the CA1 subfield of the hippocampus, which is of central importance for spatial learning and memory processes [30]. This approach allowed us to identify compensatory mechanisms of neuronal and circuit excitability, which may likely contribute to the dysfunctions found in Alzheimer’s disease where both RyR2 downregulation and altered network excitability has been reliably observed

Results

Discussion

Materials and methods

Compliance with ethical standards