Calcium channel subtypes on glutamatergic mossy fiber terminals synapsing onto rat hippocampal CA3 neurons

Shin, Min-Chul; Nonaka, Kiku; Yamaga, Toshitaka; Wakita, Masahito; Akaike, Hironari; Akaike, Norio

doi:10.1152/jn.00571.2017

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…In glutamatergic mossy fibre terminal input onto the hippocampal CA3 neurons, the voltage‐depended Ca 2+ channel currents mainly depend on P/Q‐ and N‐type channels and partially on L‐ and R‐types (Shin et al . ). Murakami et al .…”

Section: Discussionmentioning

confidence: 97%

“…In glutamatergic mossy fibre terminal input onto the hippocampal CA3 neurons, the voltage-depended Ca 2+ channel currents mainly depend on P/Q-and N-type channels and partially on L-and R-types (Shin et al 2018). Murakami et al (2002) also found that L-, P/Qand N-type channels in rat hippocampal neurons mainly have functional roles in the GABAergic nerve terminal.…”

Section: Effects Of Xe On I Na and I Bamentioning

confidence: 93%

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Xenon modulates synaptic transmission to rat hippocampal CA3 neurons at both pre‐ and postsynaptic sites

Nonaka

Kotani²,

Akaike

et al. 2019

The Journal of Physiology

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Key points Xenon (Xe) non‐competitively inhibited whole‐cell excitatory glutamatergic current (IGlu) and whole‐cell currents gated by ionotropic glutamate receptors (IAMPA, IKA, INMDA), but had no effect on inhibitory GABAergic whole‐cell current (IGABA). Xe decreased only the frequency of glutamatergic spontaneous and miniature excitatory postsynaptic currents and GABAergic spontaneous inhibitory postsynaptic currents without changing the amplitude or decay times of these synaptic responses. Xe decreased the amplitude of both the action potential‐evoked excitatory and the action potential‐evoked inhibitory postsynaptic currents (eEPSCs and eIPSCs, respectively) via a presynaptic inhibition in transmitter release. We conclude that the main site of action of Xe is presynaptic in both excitatory and inhibitory synapses, and that the Xe inhibition is much greater for eEPSCs than for eIPSCs. Abstract To clarify how xenon (Xe) modulates excitatory and inhibitory whole‐cell and synaptic responses, we conducted an electrophysiological experiment using the ‘synapse bouton preparation’ dissociated mechanically from the rat hippocampal CA3 region. This technique can evaluate pure single‐ or multi‐synapse responses and enabled us to accurately quantify how Xe influences pre‐ and postsynaptic aspects of synaptic transmission. Xe inhibited whole‐cell glutamatergic current (IGlu) and whole‐cell currents gated by the three subtypes of glutamate receptor (IAMPA, IKA and INMDA). Inhibition of these ionotropic currents occurred in a concentration‐dependent, non‐competitive and voltage‐independent manner. Xe markedly depressed the slow steady current component of IAMPA almost without altering the fast phasic IAMPA component non‐desensitized by cyclothiazide. It decreased current frequency without affecting the amplitude and current kinetics of glutamatergic spontaneous excitatory postsynaptic currents and miniature excitatory postsynaptic currents. It decreased the amplitude, increasing the failure rate (Rf) and paired‐pulse rate (PPR) without altering the current kinetics of glutamatergic action potential‐evoked excitatory postsynaptic currents. Thus, Xe has a clear presynaptic effect on excitatory synaptic transmission. Xe did not alter the GABA‐induced whole‐cell current (IGABA). It decreased the frequency of GABAergic spontaneous inhibitory postsynaptic currents without changing the amplitude and current kinetics. It decreased the amplitude and increased the PPR and Rf of the GABAergic action potential‐evoked inhibitory postsynaptic currents without altering the current kinetics. Thus, Xe acts exclusively at presynaptic sites at the GABAergic synapse. In conclusion, our data indicate that a presynaptic decrease of excitatory transmission is likely to be the major mechanism by which Xe induces anaesthesia, with little contribution of effects on GABAergic synapses.

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Section: Discussionmentioning

confidence: 97%

Section: Effects Of Xe On I Na and I Bamentioning

confidence: 93%

Xenon modulates synaptic transmission to rat hippocampal CA3 neurons at both pre‐ and postsynaptic sites

Nonaka

Kotani²,

Akaike

et al. 2019

The Journal of Physiology

Self Cite

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“…These data reveal a powerful mechanism by which stress impairs dlPFC cognitive function, and also suggest that either loss-of-function or gain-of-function variants in CACNA1C would be harmful to dlPFC function and increase risk of neuropsychiatric disorders. As LTCCs are often found to have only excitatory effects on neuronal firing, the loss of dlPFC neuronal firing with excessive LTCC actions via SK potassium channel opening is particularly noteworthy, especially as KCNN3 SK3 channels are preferentially enriched in dlPFC CALB1 -expressing excitatory cells in the human dlPFC. Thus, these cells may be especially vulnerable to loss of firing under conditions of high calcium.…”

Section: Discussionmentioning

confidence: 97%

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders

Datta,

Yang,

Joyce

et al. 2024

JAMA Psychiatry

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ImportanceThe risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders.ObjectiveTo examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices.Design, Setting, and ParticipantsThe design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques.Main Outcomes and MeasuresOutcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments.ResultsLayer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress.Conclusions and RelevanceThe layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.

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“…As in most other synapses, vesicle release at the MF terminal depends on Ca 2+ influx through voltage-dependent calcium channels (VGCC), such as the P/Q-, N-, L-, and R-type calcium channels ( Li et al, 2007 ; Vyleta and Jonas, 2014 ; Shin et al, 2018 ). In addition, the activation of presynaptic NMDA receptors during high frequency activity ( Carta et al, 2018 ; Lituma et al, 2021 ) and release of Ca 2+ from internal stores ( Lauri et al, 2003 ; Scott and Rusakov, 2006 ) also contribute to Ca 2+ dynamics at the MF synapse.…”

Section: The Role Of Ca 2+ and Adenylyl Cyclase 1 ...mentioning

confidence: 99%

cAMP-Dependent Synaptic Plasticity at the Hippocampal Mossy Fiber Terminal

Shahoha

Cohen

Ben-Simon

et al. 2022

Front. Synaptic Neurosci.

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Cyclic adenosine monophosphate (cAMP) is a crucial second messenger involved in both pre- and postsynaptic plasticity in many neuronal types across species. In the hippocampal mossy fiber (MF) synapse, cAMP mediates presynaptic long-term potentiation and depression. The main cAMP-dependent signaling pathway linked to MF synaptic plasticity acts via the activation of the protein kinase A (PKA) molecular cascade. Accordingly, various downstream putative synaptic PKA target proteins have been linked to cAMP-dependent MF synaptic plasticity, such as synapsin, rabphilin, synaptotagmin-12, RIM1a, tomosyn, and P/Q-type calcium channels. Regulating the expression of some of these proteins alters synaptic release probability and calcium channel clustering, resulting in short- and long-term changes to synaptic efficacy. However, despite decades of research, the exact molecular mechanisms by which cAMP and PKA exert their influences in MF terminals remain largely unknown. Here, we review current knowledge of different cAMP catalysts and potential downstream PKA-dependent molecular cascades, in addition to non-canonical cAMP-dependent but PKA-independent cascades, which might serve as alternative, compensatory or competing pathways to the canonical PKA cascade. Since several other central synapses share a similar form of presynaptic plasticity with the MF, a better description of the molecular mechanisms governing MF plasticity could be key to understanding the relationship between the transcriptional and computational levels across brain regions.

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Calcium channel subtypes on glutamatergic mossy fiber terminals synapsing onto rat hippocampal CA3 neurons

Cited by 8 publications

References 28 publications

Xenon modulates synaptic transmission to rat hippocampal CA3 neurons at both pre‐ and postsynaptic sites

Xenon modulates synaptic transmission to rat hippocampal CA3 neurons at both pre‐ and postsynaptic sites

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders

cAMP-Dependent Synaptic Plasticity at the Hippocampal Mossy Fiber Terminal

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