Calcium channelopathies and intellectual disability: a systematic review

Kessi, Miriam; Chen, Baiyu; Peng, Jing; Yan, Fangling; Yang, Lifen; Yin, Fei

doi:10.1186/s13023-021-01850-0

Cited by 52 publications

(41 citation statements)

References 302 publications

(381 reference statements)

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“…Tambasco et al ( 2) also showed that SS was a congenital disorder. Additionally, the neurological channelopathies, which are similar manifestations to SS, have been confirmed as a rare monogenic genetic disease, and a variety of mutant genes, such as SCN, KCNQ, KCNA, CHRNA, GABRB, etc., have been reported (49)(50)(51)(52). This also supports that SS may be a genetic disease.…”

Section: Genetic Factorssupporting

confidence: 68%

A new perspective of hypothalamic disease: Shapiro's syndrome

et al. 2022

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Shapiro's syndrome (SS) is characterized by spontaneous periodic hypothermia. It occurs to patients regardless of age or sex. To date, <60 cases have been reported worldwide. Current knowledge of the disease is limited to clinical feature since the pathogenesis and etiology are still controversial. In this review, the clinical characteristics, pathological mechanism, and possible etiology of the syndrome were reviewed to improve the clinical understanding of the disease.

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Section: Genetic Factorssupporting

confidence: 68%

A new perspective of hypothalamic disease: Shapiro's syndrome

et al. 2022

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“…In addition, T-type calcium channels play a central role in either tonic or burst firing of thalamic neurons 84 and T-type calcium blockade can modulate theta/alpha oscillations in the human brain 23 . The contribution of calcium channelopathies is increasingly recognized in intellectual disability syndromes 85 , including known alterations in T-type calcium channels in FXS 29 . This raises speculation for new avenues of therapeutics, including targeting ion channels and non-invasive perturbation channels, to understand mechanisms that promote and maintain suboptimal brain states.…”

Section: Discussionmentioning

confidence: 99%

Neocortical localization and thalamocortical modulation of neuronal hyperexcitability contribute to Fragile X Syndrome

et al. 2022

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Fragile X Syndrome (FXS) is a monogenetic form of intellectual disability and autism in which well-established knockout (KO) animal models point to neuronal hyperexcitability and abnormal gamma-frequency physiology as a basis for key disorder features. Translating these findings into patients may identify tractable treatment targets. Using source modeling of resting-state electroencephalography data, we report findings in FXS, including 1) increases in localized gamma activity, 2) pervasive changes of theta/alpha activity, indicative of disrupted thalamocortical modulation coupled with elevated gamma power, 3) stepwise moderation of low and high-frequency abnormalities based on female sex, and 4) relationship of this physiology to intellectual disability and neuropsychiatric symptoms. Our observations extend findings in Fmr1−/− KO mice to patients with FXS and raise a key role for disrupted thalamocortical modulation in local hyperexcitability. This systems-level mechanism has received limited preclinical attention but has implications for understanding fundamental disease mechanisms.

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“…Finally, there are reports of changes to ion-channel properties and intrinsic properties spanning different neuronal subtypes under several pathophysiological and altered behavioral conditions (Kullmann and Waxman, 2010; Terzic and Perez-Terzic, 2010; Cannon, 2021; Deng and Klyachko, 2021; Franklin and Laubham, 2021; Gripp et al, 2021; Kessi et al, 2021; Mantegazza et al, 2021). Thus, future studies should explore the impact of altered channel properties/densities under different behavioral and pathological conditions on specific ion channels and the physiology of SCN neurons, as well as the impact on transitions and plasticity manifolds associated with them.…”

Section: Discussionmentioning

confidence: 99%

Plasticity manifolds and ion-channel degeneracy govern circadian oscillations of neuronal intrinsic properties in the suprachiasmatic nucleus

Nagaraj

Narayanan

2022

Preprint

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Motivation and methods: The suprachiasmatic nucleus (SCN) is the master circadian clock of the mammalian brain that sustains a neural code for circadian time through oscillations in the firing rate of constituent neurons. These cell-autonomous oscillations in intrinsic properties are mediated by plasticity in a subset of ion-channels expressed in SCN neurons and are maintained despite widespread neuron-to-neuron variability in ion channel expression profiles. How do SCN neurons undergo stable transitions and maintain precision in intrinsic properties spanning the day-night cycle if several ion channels change concomitantly in a heterogeneous neuronal population? Here, we address this important question using unbiased stochastic searches on the parametric and the plasticity spaces using populations of SCN models, each explored for multiple valid transitions spanning one complete circadian cycle (day-to-night followed by night-to-day transitions). Results: Our analyses provided three fundamental insights about the impact of heterogeneities on the circadian oscillations of SCN intrinsic properties. First, SCN neurons could achieve signature electrophysiological characteristics (day-like or night-like) despite pronounced heterogeneity in ion channel conductances, with weak pairwise correlations between their conductance values. This ion-channel degeneracy precluded the need to maintain precise ion-channel expression profiles for achieving characteristic electrophysiological signatures of SCN neurons, thus allowing for parametric heterogeneities despite functional precision. Second, it was not essential that specific conductances had to change by precise values for obtaining valid day-to-night or night-to-day transitions. This plasticity degeneracy, the ability of disparate combinations of ion-channel plasticity to yield the same functional transition, confers flexibility on individual neurons to take one of several routes to achieve valid transitions. Finally, we performed nonlinear dimensionality reduction analyses on the valid plasticity spaces and found the manifestation of a low-dimensional plasticity manifold in day-to-night transitions, but not in night-to-day transitions. These observations demonstrated that the concomitant changes in multiple ion channels are not arbitrary, but follow a structured plasticity manifold that provides a substrate for stability in achieving stable circadian oscillations. Implications: Our analyses unveil an elegant substrate, involving a synthesis of the degeneracy and the plasticity manifold frameworks, to effectuate stable circadian oscillations in a heterogeneous population of SCN neurons. Within this framework, the ability of multiple ion channels to change concomitantly provides robustness and flexibility to effectively achieve precise transitions despite widespread heterogeneities in ion-channel expression and plasticity.

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Calcium channelopathies and intellectual disability: a systematic review

Cited by 52 publications

References 302 publications

A new perspective of hypothalamic disease: Shapiro's syndrome

A new perspective of hypothalamic disease: Shapiro's syndrome

Neocortical localization and thalamocortical modulation of neuronal hyperexcitability contribute to Fragile X Syndrome

Plasticity manifolds and ion-channel degeneracy govern circadian oscillations of neuronal intrinsic properties in the suprachiasmatic nucleus

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