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

Abstract

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, postdevelopmental 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.

RyR-mediated Ca2+release elicited by neuronal activity induces nuclear Ca2+signals, CREB phosphorylation, and Npas4/RyR2 expression

“…Recent reports have highlighted the pivotal role of RyR2-mediated Ca 2+ release in dendritic spine remodeling and hippocampal-dependent memory processes (34). Both in vitro and in vivo experiments have confirmed the central role RyR2 channels play in the maintenance and remodeling of dendritic spines, since their loss results in compensatory increases in neuronal excitability and hyperactivity (35). Moreover, neuronal RyR2 channels interact with the L-type Cav1.3 channels; this structural and functional cluster was proposed to have a role in translating synaptic activity into gene expression changes (51).…”

“…The contribution of RyR2 channels to nuclear Ca 2+ signal generation has not been reported, even though the RyR2 isoform plays key roles in hippocampal structural plasticity and spatial memory processes (34). Moreover, RyR2 loss impairs neuronal activity-dependent remodeling of dendritic spines and triggers compensatory neuronal hyperexcitability (35). We have reported previously that the RyR2 protein content is higher than that of RyR3 and IP 3 R1 both in rat hippocampal primary cultures and in the whole rat hippocampus (36).…”

Limiting RyR2 open time prevents Alzheimer's disease‐related deficits in the 3xTG‐AD mouse model

“…Indeed, it has recently been shown that the loss of RyR2 in the hippocampal pyramidal neurons impaired the maintenance of dendritic spines and activity‐evoked spine plasticity. Furthermore, postdevelopmental deletion of RyR2 resulted in the loss of excitatory synapses, network hyperactivity, and disruption of spatially tuned place cells (Bertan et al., 2020). Moreover, RyR2 downregulation via antisense oligodeoxynucleotides abolished brain‐derived neurotrophic factor (BDNF)‐induced dendritic spine remodeling in cultured hippocampal neurons and severely affected spatial memory (More et al., 2018).…”

“Ryanopathies” and RyR2 dysfunctions: can we further decipher them using in vitro human disease models?

“…Dendritic sparsification, loss of excitatory synapses and over compensatory excitability were also observed. These alterations suggest a crucial role of RyR2 in neurodegenerative diseases [ 93 ].…”