Genetic Calcium Signaling Abnormalities in the Central Nervous System: Seizures, Migraine, and Autism

Abstract

The calcium ion is one of the most versatile, ancient, and universal of biological signaling molecules, known to regulate physiological systems at every level from membrane potential and ion transporters to kinases and transcription factors. Disruptions of intracellular calcium homeostasis underlie a host of emerging diseases, the calciumopathies. Cytosolic calcium signals originate either as extracellular calcium enters through plasma membrane ion channels or from the release of an intracellular store in the endoplasmic reticulum (ER) via inositol triphosphate receptor and ryanodine receptor channels. Therefore, to a large extent, calciumopathies represent a subset of the channelopathies, but include regulatory pathways and the mitochondria, the major intracellular calcium repository that dynamically participates with the ER stores in calcium signaling, thereby integrating cellular energy metabolism into these pathways, a process of emerging importance in the analysis of the neurodegenerative and neuropsychiatric diseases. Many of the calciumopathies are common complex polygenic diseases, but leads to their understanding come most prominently from rare monogenic channelopathy paradigms. Monogenic forms of common neuronal disease phenotypes-such as seizures, ataxia, and migraine-produce a constitutionally hyperexcitable tissue that is susceptible to periodic decompensations. The gene families and genetic lesions underlying familial hemiplegic migraine, FHM1/CACNA1A, FHM2/ATP1A2, and FHM3/SCN1A, and monogenic mitochondrial migraine syndromes, provide a robust platform from which genes, such as CACNA1C, which encodes the calcium channel mutated in Timothy syndrome, can be evaluated for their role in autism and bipolar disease.

Neural network modelling of the influence of channelopathies on reflex visual attention

“…Many types of channelopathies may have similar influence on neural dynamics, leading to a great heterogeneity of symptoms in autism spectrum disorder and other attention-related disorders. In particular the role of calcium signaling abnormalities, linked to the L-type voltage-gated calcium channelopathies, has been documented in the literature (McEnery et al 1998;Gargus 2009;Splawski et al 2004;Krey and Dolmetsch 2007). This hypothesis of the etiology of ASD and other disorders is modelled at the neural network level changing the biophysical properties of neurons to reflect influence of channelopathies on neural dynamics.…”

“…The body of evidence on these calcium signalling pathways anomalies in the neurons of autistic subjects consists primarily in a growing corpus of genetic studies. Indeed, the genetic evidence linking autism and calcium channelopathies is clear, as exposed by Gargus (2009). However, the exact nature of that link is not yet understood.…”

“…Existing studies hypothesised the emergent attentional effects of specific calcium channels defects as a possible root cause for some symptoms observed in cases of autism and autism spectrum disorders. They have indicated that calcium channelopathies may be common occurrences in autistic subjects (Lu et al 2012;Gargus 2009). …”

“…Specifically, our working hypothesis of channelopathy is primarily justified by the recent linkage of defects in a subtype of VGCC called L-type voltage-gated calcium channels (LTCC) with the Timothy syndrome, a well-known channelopathy. The Timothy syndrome is notable for being one of the rare monogenic channelopathy paradigms, and furthermore presents core autism as a major symptom (Gargus 2009). Notably, the Timothy syndrome is a condition proven to be caused by the mutation of a gene (CACNA1C) encoding a sub-unit of LTCC (Splawski et al 2004), and as such is proven to be the root cause of an autism-causing voltage-gated calcium channelopathy.…”

Specific Triggers of Migraine Headache in Adolescents

“…Exact cause of migraine is unknown. There are no laboratory based diagnostic tests to identify acute migraine attack, as well as no tests to recognize migraine headache sufferers [2]. There is not enough knowledge of age dependent specific signs and symptoms, to clearly distinguish all clinical entities of adolescent migraine syndrome.…”