Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders

Heyes, Samuel; Pratt, Wendy S.; Rees, Elliott; Dahimène, Shehrazade; Ferron, Laurent; Owen, Michael John; Dolphin, Annette C.

doi:10.1016/j.pneurobio.2015.09.002

Cited by 196 publications

(169 citation statements)

References 261 publications

(342 reference statements)

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“…While the association of common and rare alleles of several VGCC subunits with schizophrenia risk is well established 17,35 , a consensus on whether they result in a loss or gain of function, and on how they may exert an effect on synapses is currently lacking 35 . Our findings suggest that CACNB4 overexpression depresses the calcium currents that drive spine formation and/or stabilization.…”

Section: Discussionmentioning

confidence: 99%

Selective Loss of Smaller Spines in Schizophrenia

MacDonald

Alhassan

Newman

et al. 2017

AJP

109

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Objective Deceased density of dendritic spines in adult schizophrenia subjects has been hypothesized to result from increased pruning of excess synapses in adolescence. In vivo imaging studies have confirmed that synaptic pruning is largely driven by the loss of large/mature synapses. Thus, increased pruning throughout adolescence would likely result in a deficit of large spines in adulthood. Here, we examined the density and volume of dendritic spines in deep layer 3 auditory cortex of 20 schizophrenia and matched control subjects as well as aberrant voltage-gated calcium channel subunit protein expression linked to spine loss. Methods Primary auditory cortex deep layer 3 spine density and volume was assessed in 20 pairs of schizophrenia and matched comparison subjects in an initial and replication cohort (12 and 8 pairs) by immunohistochemistry-confocal microscopy. Targeted Mass Spectrometry was used to quantify postsynaptic density and voltage-gated calcium channel protein expression. The effect of increased voltage-gated calcium channel subunit protein expression on spine density and volume was assessed in primary rat neuronal culture. Findings Only the smallest spines are lost in deep layer 3 primary auditory cortex of schizophrenia, while larger spines are retained. Levels of the tryptic peptide ALFDFLK, found in the schizophrenia risk gene CACNB4, inversely correlated with the density of smaller, but not larger, spines in schizophrenia subjects. Consistent with this observation, CACNB4 overexpression resulted in a lower density of smaller spines in primary neuronal cultures. Conclusion These findings require a rethinking of the over pruning hypothesis, demonstrate a link between small spine loss and a schizophrenia risk gene, and should spur more in-depth investigations of the mechanisms that govern new/small spine generation and stabilization under normal conditions as well as how this process is impaired in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Selective Loss of Smaller Spines in Schizophrenia

MacDonald

Alhassan

Newman

et al. 2017

AJP

109

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“…Mutation or dysfunction of a2d subunits has been associated with convulsive and neuropsychiatric disorders as well as with night blindness and cardiovascular dysfunction (Heyes et al, 2015;Dolphin, 2016). These observations relate directly to the use of gabapentinoids as anticonvulsants Offord and Isom, 2015).…”

Section: Physiologic Roles Of A2d Subunitsmentioning

confidence: 99%

Etiology and Pharmacology of Neuropathic Pain

Alles¹,

Smith²

2018

Pharmacological Reviews

314

251

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“…Both of HVA and LVA channels control the passive flow of Ca 2+ across membranes. Therefore, alteration in their components leads to defective channel function that translates themselves into a variety of neurological disorders including hemiplegic migraine, episodic and spinocerebellar ataxia, epilepsy, and ASD (Bidaud, Mezghrani, Swayne, Monteil, & Lory, 2006; Breitenkamp, Matthes, & Herzig, 2015; Heyes et al., 2015; Parellada et al., 2014; Stary et al., 2008; Zamponi, 2016). …”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders

Cited by 196 publications

References 261 publications

Selective Loss of Smaller Spines in Schizophrenia

Selective Loss of Smaller Spines in Schizophrenia

Etiology and Pharmacology of Neuropathic Pain

Autism throughout genetics: Perusal of the implication of ion channels

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