LIM Domain Only 4 (LMO4) Regulates Calcium-Induced Calcium Release and Synaptic Plasticity in the Hippocampus

Qin, Zhaohong; Zhou, Xun; Gomez-Smith, Mariana; Pandey, Nihar R.; Lee, Kevin F. H.; Lagace, Diane C.; Béı̈que, Jean-Claude; Chen, Hsiao‐Huei

doi:10.1523/jneurosci.6271-11.2012

Cited by 41 publications

(33 citation statements)

References 60 publications

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“…Notably, Aβ 42 increases expression of LMO4, thus providing a direct mechanism for increased RyR2 in AD brains [6]. Likewise, knockout of LMO4 reduces RyR-mediated Ca 2+ signaling and reduces its facilitation of CA3-CA1 glutamatergic synaptic transmission and LTP [124]. Because the molecular and protein machinery are uniquely aligned for synaptic RyR2 expression, these collective findings reveal a previously unappreciated role of RyR2 dysregulation in AD pathophysiology and synaptic degeneration.…”

Section: Early Transcriptomic and Proteomic Evidencementioning

confidence: 99%

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Briggs

Chakroborty

Stutzmann

2017

Biochemical and Biophysical Research Communications

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The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca2+ signaling disruptions, and focus on its role in driving synaptic deficits – which is the feature that does correlate with AD-associated memory loss. Excess Ca2+release from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IP3R and RyR, and the recent emphasis on RyR2. Consistent with ER Ca2+ mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca2+-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.

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Section: Early Transcriptomic and Proteomic Evidencementioning

confidence: 99%

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Briggs

Chakroborty

Stutzmann

2017

Biochemical and Biophysical Research Communications

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“…Along with synaptic effects, we found that the RQ mutation significantly increased postspike AHP in cortical neurons. In the absence of increased GABA release, enhancement of the late AHP is likely due to increased activation of Ca 2+ -sensitive potassium (SK) channels (46). Increased neuronal AHP limits repetitive highfrequency firing and might explain why seizures are rare in the RQ mouse.…”

Section: Rq Mutation Selectively Enhances Excitatory Synaptic Transmimentioning

confidence: 99%

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Aiba

Wehrens

Noebels

2016

Proc. Natl. Acad. Sci. U.S.A.

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Cardiorespiratory failure is the most common cause of sudden unexplained death in epilepsy (SUDEP). Genetic autopsies have detected "leaky" gain-of-function mutations in the ryanodine receptor-2 (RyR2) gene in both SUDEP and sudden cardiac death cases linked to catecholaminergic polymorphic ventricular tachycardia that feature lethal cardiac arrhythmias without structural abnormality. Here we find that a human leaky RyR2 mutation, R176Q (RQ), alters neurotransmitter release probability in mice and significantly lowers the threshold for spreading depolarization (SD) in dorsal medulla, leading to cardiorespiratory collapse. Rare episodes of sinus bradycardia, spontaneous seizure, and sudden death were detected in RQ/+ mutant mice in vivo; however, when provoked, cortical seizures frequently led to apneas, brainstem SD, cardiorespiratory failure, and death. In vitro studies revealed that the RQ mutation selectively strengthened excitatory, but not inhibitory, synapses and facilitated SD in both the neocortex as well as brainstem dorsal medulla autonomic microcircuits. These data link defects in neuronal intracellular calcium homeostasis to the vulnerability of central autonomic brainstem pathways to hypoxic stress and implicate brainstem SD as a previously unrecognized site and mechanism contributing to premature death in individuals with leaky RYR2 mutations.sudden unexpected death in epilepsy | SUDEP | catecholaminergic polymorphic ventricular tachycardia | CPVT | ryanodine receptor U p to 10% of individuals with seizures of unknown cause and without known structural cardiac pathology die of sudden unexpected death in epilepsy (SUDEP), and this morbidity is second only to stroke in the number of life-years lost (1). Despite the high mortality rate, comparable to that of sudden infant death syndrome (SIDS), the exact causes are unclear, and there is no effective prediction or intervention. Cardiorespiratory dysfunction and collapse have been observed following generalized tonicclonic seizures in a small number of monitored cases (2), "near SUDEP" cases (3), and mouse SUDEP models (4-6). Genes linked with the most common cardiac LQT syndromes including LQT1 (KCNQ1), LQT2 (KCNH2/HERG), and LQT3 (SCN5A) are expressed in both the human heart and brain, where mutations in the kinetics of these membrane ion channels prolong depolarization and produce combined seizure, cardiac arrhythmia, and sudden death phenotypes (7,8). Because mutations in these ion channel genes currently explain only a small fraction of SUDEP cases (7), the search for additional genes and mechanisms is a high priority to understand and treat sudden death risk.Along with cardiac arrhythmia, recent findings in voltage-gated ion channelopathy models point to an extracardiac, central autonomic involvement of these genes in the events leading to sudden cardiac death. Spreading depolarization (SD) is a slow propagating wave of cellular depolarization that occurs in human brain and is known to contribute to transient neurological deficits during migraine ...

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“…The IsAHP is manifested as a slow-rising and decaying outward current activated by the influx of calcium after the return of the membrane potential to À55 mV (1). In CA3 neurons, this calcium influx also triggers calcium-induced calcium release from internal stores, further prolonging the sAHP (30,31). We recorded the IsAHP in the presence of 100 nM apamin to block calcium-activated SK channels because their deactivation might have overlapped with the IsAHP activation.…”

Section: Kcnq3 Channels Are Critical For the Pyramidal Neuron Sahp Cumentioning

confidence: 99%

The Voltage Activation of Cortical KCNQ Channels Depends on Global PIP2 Levels

Kim

Duignan

Hawryluk

et al. 2016

Biophysical Journal

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The slow afterhyperpolarization (sAHP) is a calcium-activated potassium conductance with critical roles in multiple physiological processes. Pharmacological and genetic data suggest that KCNQ channels partly mediate the sAHP. However, these channels are not typically open within the observed voltage range of the sAHP. Recent work has shown that the sAHP is gated by increased PIP2 levels, which are generated downstream of calcium binding by neuronal calcium sensors such as hippocalcin. Here, we examined whether changes in PIP2 levels could shift the voltage-activation range of KCNQ channels. In HEK293T cells, expression of the PIP5 kinase PIPKIγ90, which increases global PIP2 levels, shifted the KCNQ voltage activation to within the operating range of the sAHP. Further, the sensitivity of this effect on KCNQ3 channels appeared to be higher than that on KCNQ2. Therefore, we predict that KCNQ3 plays an essential role in maintaining the sAHP under low PIP2 conditions. In support of this notion, we find that sAHP inhibition by muscarinic receptors that increase phosphoinositide turnover in neurons is enhanced in Kcnq3-knockout mice. Likewise, the presence of KCNQ3 is essential for maintaining the sAHP when hippocalcin is ablated, a condition that likely impairs PIP2 generation. Together, our results establish the relationship between PIP2 and the voltage dependence of cortical KCNQ channels (KCNQ2/3, KCNQ3/5, and KCNQ5), and suggest a possible mechanism for the involvement of KCNQ channels in the sAHP.

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LIM Domain Only 4 (LMO4) Regulates Calcium-Induced Calcium Release and Synaptic Plasticity in the Hippocampus

Cited by 41 publications

References 60 publications

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

The Voltage Activation of Cortical KCNQ Channels Depends on Global PIP2 Levels

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