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CNS Voltage-gated Calcium Channel Gene Variation And Prolonged Recovery Following Sport-related Concussion

ABSTRACT: Objectives: To examine the association between concussion duration and two calcium channel, voltage-dependent, R type, alpha 1E subunit (CACNA1E) single nucleotide polymorphisms (i.e., rs35737760 and rs704326). A secondary purpose was to examine the association between CACNA1E single nucleotide polymorphisms (SNPs) and three acute concussion severity scores (i.e., vestibule-ocular reflex test, balance error scoring scale, and Immediate Post-Concussion Assessment and Cognitive Testing). Methods: Forty athletes with a diagnosed concussion from a hospital concussion program completed a standardized initial evaluation. Concussion injury characteristics, acute signs and symptoms followed by an objective screening (i.e., vestibular ocular assessments, balance error scoring system test, and Immediate Post-Concussion Assessment and Cognitive Testing exam) were assessed. Enrolled participants provided salivary samples for isolation of DNA. Two exon SNPs rs35737760 and rs704326 within CACNA1E were genotyped. Results: There was a significant difference found between acute balance deficits and prolonged recovery group (X2 = 5.66, p = 0.017). There was an association found between the dominant model GG genotype (X2 = 5.41, p = 0.027) within the rs704326 SNP and prolonged recovery group. Significant differences were identified for the rs704326 SNP within the dominant model GG genotype (p = 0.030) for VOR scores by recovery. A significant difference was found between the rs704326 SNP codominant model AA (p = 0.042) and visual memory. There was an association between acute balance deficits and prolonged recovery (X2 = 5.66, p = 0.017) for the rs35737760 SNP. No significant associations between concussion severity and genotype for rs35737760 SNP. Conclusion: Athletes carrying the CACNA1E rs704326 homozygous genotype GG are at a greater risk of a prolonged recovery. Athletes that reported balance deficits at the time of injury were more likely to have prolonged recovery. These polymorphisms within CACNA1E could alter the CACNA1E protein and allow for an increase of calcium leading to deficits to the granule cells within the brain.

SUBMITTER: McDevitt J

PROVIDER: S-EPMC4901914 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Project description:L-type voltage-gated calcium channels (LTCCs) are implicated in several psychiatric disorders that are comorbid with alcoholism and involve amygdala dysfunction. Within the amygdala, the central nucleus (CeA) is critical in acute alcohol's reinforcing actions, and its dysregulation in human alcoholics drives their negative emotional state and motivation to drink. Here we investigated the specific role of CeA LTCCs in the effects of acute alcohol at the molecular, cellular physiology, and behavioral levels, and their potential neuroadaptation in alcohol-dependent rats. Alcohol increases CeA activity (neuronal firing rates and GABA release) in naive rats by engaging LTCCs, and intra-CeA LTCC blockade reduces alcohol intake in nondependent rats. Alcohol dependence reduces CeA LTCC membrane abundance and disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. Collectively, our data indicate that alcohol dependence functionally alters the molecular mechanisms underlying the CeA's response to alcohol (from LTCC- to CRF1-driven). This mechanistic switch contributes to and reflects the prominent role of the CeA in the negative emotional state that drives excessive drinking.SIGNIFICANCE STATEMENT The central amygdala (CeA) plays a critical role in the development of alcohol dependence. As a result, much preclinical alcohol research aims to identify relevant CeA neuroadaptions that promote the transition to dependence. Here we report that acute alcohol increases CeA neuronal activity in naive rats by engaging L-type calcium channels (LTCCs) and that intra-CeA LTCC blockade reduces alcohol intake in nondependent rats. Alcohol dependence disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. This switch reflects the important role of the CeA in the pathophysiology of alcohol dependence and represents a new potential avenue for therapeutic intervention during the transition period.

Project description:Objectives: The objective of this study was to assess if injury-related alterations in the Sport Concussion Assessment Tool-5 (SCAT5) are matched by changes in transcranial magnetic stimulation-derived intracortical inhibition. We hypothesised that neurophysiological measures would take longer to return to normal than recovery assessed by the SCAT5 following sport related concussion (SRC). Methods: Thirteen male contact sport athletes (20.5 ± 4.5 years), who reported a concussion were recruited from local Rugby and American football clubs. Participants were tested at 4 timepoints throughout the concussion recovery period: within 24 h of concussion (day 0), and at 7, 9, and 11 days after concussion. All participants completed the SCAT5 and underwent TMS to assess cortical silent period duration (CSp), a measure of intracortical inhibition. Results: After concussion CSp significantly declined from day 0 (122 ± 28 ms) to day 11 (106 ± 15 ms) [F (3, 33) = 7.80, p < 0.001]. SCAT5 measures of symptom number and severity were significantly decreased [symptom number: χ(3)2 = 30.44, p < 0.01; symptom severity: χ(3)2 = 25.75, p < 0.001] between the day 0 timepoint and each of the other timepoints. SCAT5 balance errors (mBESS) decreased significantly [F (3, 33) = 19.55, p < 0.001] between the day 0 timepoint and each of the other timepoints. CSp and SCAT5 recovery patterns were different. SCAT5 domains recovered faster showing no further significant changes after day 7, whilst CSp was still decreasing between days 7 and 9. Due to the small sample size we also used a Bayesian linear model to investigate the recovery of CSp and mBESS. The posterior distribution of our Bayesian model provided evidence that CSp decreased at day 7 and it continued to decrease at day 9, unlike mBESS which decreased at day 7 and then reached a plateau. Conclusion: There are clinically important discrepancies between clinical and neurophysiological measures of concussion recovery. This finding has important implications for return to play (RTP) protocols and the prevention of complications after sport concussion.

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CNS Voltage-gated Calcium Channel Gene Variation And Prolonged Recovery Following Sport-related Concussion

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