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

• Published in: Cell death and differentiation Vol. 27; no. 12; pp. 3354 - 3373
• Main Authors: Bertan, Fabio, Wischhof, Lena, Sosulina, Liudmila, Mittag, Manuel, Dalügge, Dennis, Fornarelli, Alessandra, Gardoni, Fabrizio, Marcello, Elena, Di Luca, Monica, Fuhrmann, Martin, Remy, Stefan, Bano, Daniele, Nicotera, Pierluigi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2020; Nature Publishing Group
• Subjects: 13/109; 13/51; 14/19; 14/32; 14/69; 38/22; 38/39; 38/77; 38/90; 42/35; 631/378; 64/110; 692/699/375; 9/74; Apoptosis; Biochemistry; Biomedical and Life Sciences; Calcium (intracellular); Calcium signalling; Cell Biology; Cell Cycle Analysis; Dendritic plasticity; Dendritic spines; Excitability; Hyperactivity; Life Sciences; Neurodegenerative diseases; Pyramidal cells; Ryanodine receptors; Stem Cells; Structure-function relationships; Synaptic plasticity
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-020-0584-2

Dendritic spines are postsynaptic domains that shape structural and functional properties of neurons. Upon neuronal activity, Ca
2+
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 Ca
2+
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.