Abnormal cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans

Familial hemiplegic migraine type 1 (FHM1) is caused by gain-of-function mutations in CaV2.1 (P/Q-type) Ca2+ channels. Knockin (KI) mice carrying the FHM1 R192Q missense mutation show enhanced cortical excitatory synaptic transmission at pyramidal cell synapses but unaltered cortical inhibitory neurotransmission at fast-spiking interneuron synapses. Enhanced cortical glutamate release was shown to cause the facilitation of cortical spreading depression (CSD) in R192Q KI mice. It, however, remains unknown how other FHM1 mutations affect cortical synaptic transmission. Here, we studied neurotransmission in cortical neurons in microculture from KI mice carrying the S218L mutation, which causes a severe FHM syndrome in humans and an allele-dosage dependent facilitation of experimental CSD in KI mice, which is larger than that caused by the R192Q mutation. We show gain-of-function of excitatory neurotransmission, due to increased action-potential evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at multipolar interneuron synapses in S218L KI mice. In contrast with the larger gain-of-function of neuronal CaV2.1 current in homozygous than heterozygous S218L KI mice, the gain-of-function of evoked glutamate release, the paired-pulse ratio and the Ca2+ dependence of the EPSC were all similar in homozygous and heterozygous S218L KI mice, suggesting compensatory changes in the homozygous mice. Furthermore, we reveal a unique feature of S218L KI cortical synapses which is the presence of a fraction of mutant CaV2.1 channels being open at resting potential. Our data suggest that, while the gain-of-function of evoked glutamate release may explain the facilitation of CSD in heterozygous S218L KI mice, the further facilitation of CSD in homozygous S218L KI mice is due to other CaV2.1-dependent mechanisms, that likely include Ca2+ influx at voltages sub-threshold for action potential generation

Pentameric repeat expansions:cortical myoclonus or cortical tremor?

Functional Genomics of Muscle, Nerve and Brain Disorder

In silico phenotyping via co-training for improved phenotype prediction from genotype

Motivation: Predicting disease phenotypes from genotypes is a key challenge in medical applications in the postgenomic era. Large training datasets of patients that have been both genotyped and phenotyped are the key requisite when aiming for high prediction accuracy. With current genotyping projects producing genetic data for hundreds of thousands of patients, large-scale phenotyping has become the bottleneck in disease phenotype prediction. Results: Here we present an approach for imputing missing disease phenotypes given the genotype of a patient. Our approach is based on co-training, which predicts the phenotype of unlabeled patients based on a second class of information, e.g. clinical health record information. Augmenting training datasets by this type of in silico phenotyping can lead to significant improvements in prediction accuracy. We demonstrate this on a dataset of patients with two diagnostic types of migraine, termed migraine with aura and migraine without aura, from the International Headache Genetics Consortium. Conclusions: Imputing missing disease phenotypes for patients via co-training leads to larger training datasets and improved prediction accuracy in phenotype prediction. Availability and implementation: The code can be obtained at: http://www.bsse.ethz.ch/mlcb/research/bioinformatics-and-computational-biology/co-training.html Contact: [email protected] or [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

Specific Kinetic Alterations of Human CaV2.1 Calcium Channels Produced by Mutation S218L Causing Familial Hemiplegic Migraine and Delayed Cerebral Edema and Coma after Minor Head Trauma

Mutation S218L in the Ca(V)2.1 alpha(1) subunit of P/Q-type Ca(2+) channels produces a severe clinical phenotype in which typical attacks of familial hemiplegic migraine (FHM) triggered by minor head trauma are followed, after a lucid interval, by deep (even fatal) coma and long lasting severe cerebral edema. We investigated the functional consequences of this mutation on human Ca(V)2.1 channels expressed in human embryonic kidney 293 cells and in neurons from Ca(V)2.1 alpha(1)(-/-) mice by combining single channel and whole cell patch clamp recordings. Mutation S218L produced a shift to lower voltages of the single channel activation curve and a consequent increase of both single channel and whole cell Ba(2+) influx in both neurons and human embryonic kidney 293 cells. Compared with the other FHM-1 mutants, the S218L shows one of the largest gains of function, especially for small depolarizations, which are insufficient to open the wild-type channel. S218L channels open at voltages close to the resting potential of many neurons. Moreover, the S218L mutation has unique effects on the kinetics of inactivation of the channel because it introduces a large component of current that inactivates very slowly, and it increases the rate of recovery from inactivation. During long depolarizations at voltages that are attained during cortical spreading depression, the extent of inactivation of the S218L channel is considerably smaller than that of the wild-type channel. We discuss how the unique combination of a particularly slow inactivation during cortical spreading depression and a particularly low threshold of channel activation might lead to delayed severe cerebral edema and coma after minor head trauma

Familial hemiplegic migraine CaV2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain

<p>Abstract</p> <p>Background</p> <p>The R192Q mutation of the CACNA1A gene, encoding for the α1 subunit of voltage-gated P/Q Ca²⁺channels (Ca_v2.1), is associated with familial hemiplegic migraine-1. We investigated whether this gain-of-function mutation changed the structure and function of trigeminal neuron P2X₃receptors that are thought to be important contributors to migraine pain.</p> <p>Results</p> <p>Using in vitro trigeminal sensory neurons of a mouse genetic model knockin for the CACNA1A R192Q mutation, we performed patch clamp recording and intracellular Ca²⁺imaging that showed how these knockin ganglion neurons generated P2X₃receptor-mediated responses significantly larger than wt neurons. These enhanced effects were reversed by the Ca_v2.1 blocker ω-agatoxin. We, thus, explored intracellular signalling dependent on kinases and phosphatases to understand the molecular regulation of P2X₃receptors of knockin neurons. In such cells we observed strong activation of CaMKII reversed by ω-agatoxin treatment. The CaMKII inhibitor KN-93 blocked CaMKII phosphorylation and the hyperesponsive P2X₃phenotype. Although no significant difference in membrane expression of knockin receptors was found, serine phosphorylation of knockin P2X₃receptors was constitutively decreased and restored by KN-93. No change in threonine or tyrosine phosphorylation was detected. Finally, pharmacological inhibitors of the phosphatase calcineurin normalized the enhanced P2X₃receptor responses of knockin neurons and increased their serine phosphorylation.</p> <p>Conclusions</p> <p>The present results suggest that the CACNA1A mutation conferred a novel molecular phenotype to P2X₃receptors of trigeminal ganglion neurons via CaMKII-dependent activation of calcineurin that selectively impaired the serine phosphorylation state of such receptors, thus potentiating their effects in transducing trigeminal nociception.</p

Cerebellar output controls generalized spike-and-wave discharge occurence

© 2015 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (CC BY-NC-ND 4.0) which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizuresPeer reviewedFinal Published versio

Silencing the majority of cerebellar granule cells uncovers their essential role in motor learning and consolidation.

Cerebellar granule cells (GCs) account for more than half of all neurons in the CNS of vertebrates. Theoretical work has suggested that the abundance of GCs is advantageous for sparse coding during memory formation. Here, we minimized the output of the majority of GCs by selectively eliminating their CaV2.1 (P/Q-type) Ca2+ channels, which mediate the bulk of their neurotransmitter release. This resulted in reduced GC output to Purkinje cells (PCs) and stellate cells (SCs) as well as in impaired long-term plasticity at GC-PC synapses. As a consequence modulation amplitude and regularity of simple spike (SS) output were affected. Surprisingly, the overall motor performance was intact, whereas demanding motor learning and memory consolidation tasks were compromised. Our findings indicate that a minority of functionally intact GCs is sufficient for the maintenance of basic motor performance, whereas acquisition and stabilization of sophisticated memories require higher numbers of normal GCs controlling PC firing

Trigeminovascular calcitonin gene-related peptide function in Cacna1a R192Q-mutated knock-in mice

Familial hemiplegic migraine type 1 (FHM1) is a rare migraine subtype. Whereas transgenic knock-in mice with the human pathogenic FHM1 R192Q missense mutation in the Cacna1a gene reveal overall neuronal hyperexcitability, the effects on the trigeminovascular system and calcitonin gene-related peptide (CGRP) receptor are largely unknown. This gains relevance as blockade of CGRP and its receptor are therapeutic targets under development. Hence, we set out to test these effects in FHM1 mice. We characterized the trigeminovascular system of wild-type and FHM1 mice through: (i) in vivo capsaicin- and CGRP-induced dural vasodilation in a closed-cranial window; (ii) ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion and trigeminal nucleus caudalis; and (iii) peripheral vascular function in vitro. In mutant mice, dural vasodilatory responses were significantly decreased compared to controls. The ex vivo release of CGRP was not different in the components of the trigeminovascular system between genotypes; however, sumatriptan diminished the release in the trigeminal ganglion, trigeminal nucleus caudalis and dura mater but only in wild-type mice. Peripheral vascular function was similar between genotypes. These dat

Migraine, inflammatory bowel disease and celiac disease: A Mendelian randomization study

Objective: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease. Background: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition. Methods: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed. Results: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction. Conclusions: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes. Keywords: Mendelian randomization; celiac disease; gastrointestinal disease; genetic correlation; inflammatory bowel disease; migraine