Subcellular localization of hippocampal ryanodine receptor 2 and its role in neuronal excitability and memory

Abstract

Ryanodine receptor 2 (RyR2) is abundantly expressed in the heart and brain. Mutations in RyR2 are associated with both cardiac arrhythmias and intellectual disability. While the mechanisms of RyR2-linked arrhythmias are well characterized, little is known about the mechanism underlying RyR2-associated intellectual disability. Here, we employed a mouse model expressing a green fluorescent protein (GFP)-tagged RyR2 and a specific GFP probe to determine the subcellular localization of RyR2 in hippocampus. GFP-RyR2 was predominantly detected in the soma and dendrites, but not the dendritic spines of CA1 pyramidal neurons or dentate gyrus granular neurons. GFP-RyR2 was also detected within the mossy fibers in the stratum lucidum of CA3, but not in the presynaptic terminals of CA1 neurons. An arrhythmogenic RyR2-R4496C+/− mutation downregulated the A-type K+ current and increased membrane excitability, but had little effect on the afterhyperpolarization current or presynaptic facilitation of CA1 neurons. The RyR2-R4496C+/− mutation also impaired hippocampal long-term potentiation, learning, and memory. These data reveal the precise subcellular distribution of hippocampal RyR2 and its important role in neuronal excitability, learning, and memory.

Cytosolic calcium: Judge, jury and executioner of neurodegeneration in Alzheimer's disease and beyond

“…The IP 3 R, activated by the second messenger, IP 3 , is localized predominantly in the soma, nuclear envelope, and proximal dendrites and plays key roles in second messenger signaling, calcium‐activated gene transcription, synaptic plasticity, and cellular bioenergetics 9 . In the brain, the RyR, and predominantly the RyR2 isoform, is localized in hippocampus, cortex, and other brain regions essential for memory encoding 10,11 . It is activated by calcium itself, a process termed calcium‐induced calcium release (CICR), to further amplify Ca 2+ signaling 12 .…”

R-carvedilol, a potential new therapy for Alzheimer’s disease

“…Interestingly, RyR2, a target of carvedilol, is abundantly expressed in both the heart and the brain (Furuichi et al, 1994;Giannini et al, 1995;Murayama and Ogawa, 1996;Bers, 2002). In particular, RyR2 is abundantly expressed in the hippocampus and cortex, which are the regions most vulnerable to damage caused by AD (Yao et al, 2020;Hiess et al, 2022). Increasing evidence suggests that the expression and function of RyR2 are upregulated in animal models of familial AD (FAD) and in human AD patients (Kelliher et al, 1999;Smith et al, 2005;Bruno et al, 2012;Oules et al, 2012;Chakroborty and Stutzmann, 2014;Lacampagne et al, 2017;SanMartin et al, 2017;Stutzmann, 2021).…”

Long-term potentiation and spatial memory training stimulate the hippocampal expression of RyR2 calcium release channels

“…Neuronal Ca 2+ signals generated by Ca 2+ entry via plasma membrane Ca 2+ channels and Ca 2+ release from the endoplasmic reticulum (ER) are required for hippocampal synaptic plasticity and spatial memory processes (Verkhratsky and Shmigol, 1996 ; Raymond and Redman, 2006 ; Galeotti et al, 2008 ; Baker et al, 2013 ; Brini et al, 2014 ; Paula-Lima et al, 2014 ; More et al, 2018b ; Hiess et al, 2022 ). As presented in the Introduction section, several studies have revealed that different neuronal stimulation or memory training protocols enhance the hippocampal expression of the ER-resident RyR2 and RyR3 channel isoforms.…”

“…Several studies have implicated Ca 2+ release through RyR channels in learning and memory processes (Edwards and Rickard, 2006 ; Galeotti et al, 2008 ; Baker et al, 2010 ; Adasme et al, 2011 ; More et al, 2018b ; Hiess et al, 2022 ). Previous studies reporting increments in RyR2, RyR3, and IP 3 R1 protein content induced in rat hippocampus by spatial memory training, object location or fear conditioning protocols (Zhao et al, 2000 ; Adasme et al, 2011 ; Arias-Cavieres et al, 2017 ; More et al, 2018a , b ) suggest that these enhancements have a role in memory processes.…”