Calcium Release Mediated by Redox-Sensitive RyR2 Channels Has a Central Role in Hippocampal Structural Plasticity and Spatial Memory

More, Jamileth; Bruna, Bárbara; Lobos, Pedro; Galaz, José; Figueroa, Paula; Namias, Silvia; Sánchez, Gittith; Barrientos, Genaro; Valdés, José Luís; Paula-Lima, Andrea; Hidalgo, Cecilia; Adasme, Tatiana

doi:10.1089/ars.2017.7277

Cited by 43 publications

(59 citation statements)

References 124 publications

(152 reference statements)

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“…We suggest, accordingly, that the formation of long-term memory, or the early stages of the consolidation phase of fear-conditioned memory, requires transitory RyR2 upregulation in the whole hippocampus in order to generate the Ca 2+ signals required for fear memory consolidation. Previous reports—showing increased RyR2 upregulation in animals exposed to different hippocampal-dependent memory protocols [ 31 , 43 – 45 ]—support our proposal. These combined results place calcium release mediated by RyR2 channels and presumably RyR2 upregulation as well as important events in hippocampal-dependent memory processes.…”

Section: Discussionsupporting

confidence: 90%

“…The brain expresses all three RyR isoforms; of these, the RyR2 isoform is the predominant isoform expressed in rat and chicken brain [ 29 , 30 ]. As detailed below, the redox-sensitive RyR2 isoforms have key roles in hippocampal structural plasticity and spatial memory processes [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

“…Treatment of primary hippocampal neurons with the RyR agonist caffeine or with brain-derived neurotrophic factor (BDNF) promotes RyR-dependent dendritic spine remodeling, leading to increased density and length of dendritic spines [ 38 , 42 , 43 ]. In addition, RyR2 downregulation abolishes BDNF-induced spine remodeling in primary hippocampal neurons [ 31 ]. These findings indicate that the RyR2 isoform plays a key role in hippocampal structural plasticity.…”

Section: Introductionmentioning

confidence: 99%

“…In mice, RyR channel inhibition hampers memory retention in animals conditioned in inhibitory avoidance or radial arm-maze tasks [ 29 , 47 ], while studies involving administration to mice of antisense oligodeoxynucleotides directed at each RyR isoform indicate that selective knockdown of RyR2 and RyR3, but not of RyR1, impairs memory retention in a passive avoidance test [ 29 ]. Highlighting the key role of the RyR2 isoform in memory processes, a recent study performed in rats showed that RyR2 downregulation by intrahippocampal injection of RyR2-directed antisense oligodeoxynucleotides causes conspicuous defects in a previously memorized spatial memory task [ 31 ]. To our knowledge, however, information is lacking regarding whether fear memory formation, consolidation, or extinction entail RyR channel function or expression.…”

Section: Introductionmentioning

confidence: 99%

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Contextual Fear Memory Formation and Destabilization Induce Hippocampal RyR2 Calcium Channel Upregulation

Casas

Pecchi

et al. 2018

Neural Plasticity

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Hippocampus-dependent spatial and aversive memory processes entail Ca2+ signals generated by ryanodine receptor (RyR) Ca2+ channels residing in the endoplasmic reticulum membrane. Rodents exposed to different spatial memory tasks exhibit significant hippocampal RyR upregulation. Contextual fear conditioning generates robust hippocampal memories through an associative learning process, but the effects of contextual fear memory acquisition, consolidation, or extinction on hippocampal RyR protein levels remain unreported. Accordingly, here we investigated if exposure of male rats to contextual fear protocols, or subsequent exposure to memory destabilization protocols, modified the hippocampal content of type-2 RyR (RyR2) channels, the predominant hippocampal RyR isoforms that hold key roles in synaptic plasticity and spatial memory processes. We found that contextual memory retention caused a transient increase in hippocampal RyR2 protein levels, determined 5 h after exposure to the conditioning protocol; this increase vanished 29 h after training. Context reexposure 24 h after training, for 3, 15, or 30 min without the aversive stimulus, decreased fear memory and increased RyR2 protein levels, determined 5 h after reexposure. We propose that both fear consolidation and extinction memories induce RyR2 protein upregulation in order to generate the intracellular Ca2+ signals required for these distinct memory processes.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Contextual Fear Memory Formation and Destabilization Induce Hippocampal RyR2 Calcium Channel Upregulation

Casas

Pecchi

et al. 2018

Neural Plasticity

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“…The RyR channels, which are widely expressed in the brain (Furuichi et al, 1994 ; Zhao et al, 2000 ), play central roles in synaptic plasticity (Reyes and Stanton, 1996 ; Lu and Hawkins, 2002 ; Raymond and Redman, 2002 ; Mellentin et al, 2007 ; Grigoryan et al, 2012 ). In addition, RyR channel activation facilitates learning and memory formation whereas inhibition of RyR activity or expression impairs these processes (Zhao et al, 2000 ; Edwards and Rickard, 2006 ; Galeotti et al, 2008 ; Adasme et al, 2011 ; Hidalgo and Arias-Cavieres, 2016 ; More et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Ryanodine Receptor-Mediated Calcium Release Has a Key Role in Hippocampal LTD Induction

Arias‐Cavieres

Barrientos

Sánchez

et al. 2018

Front. Cell. Neurosci.

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The induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission entails pre- and postsynaptic Ca2+ signals, which represent transient increments in cytoplasmic free Ca2+ concentration. In diverse synapse types, Ca2+ release from intracellular stores contributes to amplify the Ca2+ signals initially generated by activation of neuronal Ca2+ entry pathways. Here, we used hippocampal slices from young male rats to evaluate whether pharmacological activation or inhibition of Ca2+ release from the endoplasmic reticulum (ER) mediated by ryanodine receptor (RyR) channels modifies LTD induction at Schaffer collateral-CA1 synapses. Pre-incubation of slices with ryanodine (1 μM, 1 h) or caffeine (1 mM, 30 min) to promote RyR-mediated Ca2+ release facilitated LTD induction by low frequency stimulation (LFS), but did not affect the amplitude of synaptic transmission, the profiles of field excitatory postsynaptic potentials (fEPSP) or the paired-pulse (PP) responses. Conversely, treatment with inhibitory ryanodine (20 μM, 1 h) to suppress RyR-mediated Ca2+ release prevented LTD induction, but did not affect baseline synaptic transmission or PP responses. Previous literature reports indicate that LTD induction requires presynaptic CaMKII activity. We found that 1 h after applying the LTD induction protocol, slices displayed a significant increase in CaMKII phosphorylation relative to the levels exhibited by un-stimulated (naïve) slices. In addition, LTD induction (1 h) enhanced the phosphorylation of the presynaptic protein Synapsin I at a CaMKII-dependent phosphorylation site, indicating that LTD induction stimulates presynaptic CaMKII activity. Pre-incubation of slices with 20 μM ryanodine abolished the increased CaMKII and Synapsin I phosphorylation induced by LTD, whereas naïve slices pre-incubated with inhibitory ryanodine displayed similar CaMKII and Synapsin I phosphorylation levels as naïve control slices. We posit that inhibitory ryanodine suppressed LTD-induced presynaptic CaMKII activity, as evidenced by the suppression of Synapsin I phosphorylation induced by LTD. Accordingly, we propose that presynaptic RyR-mediated Ca2+ signals contribute to LTD induction at Schaffer collateral-CA1 synapses.

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Increased RyR2 open probability induces neuronal hyperactivity and memory loss with or without Alzheimer's disease–causing gene mutations

Yao

Liu

Sun

et al. 2022

Alzheimer's & Dementia

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Introduction Neuronal hyperactivity is an early neuronal defect commonly observed in familial and sporadic Alzheimer's disease (AD), but the underlying mechanisms are unclear. Methods We employed a ryanodine receptor 2 (RyR2) mutant mouse model harboring the R4496C+/– mutation that markedly increases the channel's open probability (Po) to determine the impact of increased RyR2 activity in neuronal function without AD gene mutations. Results Genetically increasing RyR2 Po induced neuronal hyperactivity in vivo in anesthetized and awake mice. Increased RyR2 Po induced hyperactive behaviors, impaired learning and memory, defective dendritic spines, and neuronal cell death. Increased RyR2 Po exacerbated the onset of neuronal hyperexcitability and learning and memory impairments in 5xFAD mice. Discussion Increased RyR2 Po exacerbates the onset of familial AD–associated neuronal dysfunction, and induces AD‐like defects in the absence of AD‐causing gene mutations, suggesting that RyR2‐associated neuronal hyperactivity represents a common target for combating AD with or without AD gene mutations.

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Calcium Release Mediated by Redox-Sensitive RyR2 Channels Has a Central Role in Hippocampal Structural Plasticity and Spatial Memory

Cited by 43 publications

References 124 publications

Contextual Fear Memory Formation and Destabilization Induce Hippocampal RyR2 Calcium Channel Upregulation

Contextual Fear Memory Formation and Destabilization Induce Hippocampal RyR2 Calcium Channel Upregulation

Ryanodine Receptor-Mediated Calcium Release Has a Key Role in Hippocampal LTD Induction

Increased RyR2 open probability induces neuronal hyperactivity and memory loss with or without Alzheimer's disease–causing gene mutations

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