scholarly journals Function of Neuromuscular Synapses in the Zebrafish Choline-Acetyltransferase Mutant bajan

2008 ◽  
Vol 100 (4) ◽  
pp. 1995-2004 ◽  
Author(s):  
Meng Wang ◽  
Hua Wen ◽  
Paul Brehm
Keyword(s):  
Choline Acetyltransferase ◽  
Residual Activity ◽  
Direct Consequence ◽  
Synaptic Function ◽  
Congenital Myasthenic Syndrome ◽  
Quantal Content ◽  
Quantal Size ◽  
Gene Coding ◽  
Myasthenic Syndrome ◽  
The Impact

We have identified a zebrafish mutant line, bajan, in which compromised motility and fatigue result from a point mutation in the gene coding choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine (ACh) synthesis. Although the mutation predicts loss of ChAT function, bajan inexplicably retains low levels of neuromuscular transmission. We exploited this residual activity and determined the consequences for synaptic function. The attenuated synaptic responses were a direct consequence of a decrease in both resting mean quantal size and quantal content. To replicate behavioral fatigue in swimming, motorneurons were stimulated at high frequencies. A prominent reduction in quantal content, reflecting vesicle depletion, was coincident with a small additional reduction in quantal size. In humans, defective ChAT leads to episodic apnea, a form of congenital myasthenic syndrome characterized by use-dependent fatigue. In contrast to bajan, however, afflicted individuals exhibit a normal resting quantal size and quantal content. The fatigue in humans results from a pronounced long-lasting drop in quantal size with little or no change in quantal content. These differences have important implications for interpreting fatigue as well as on understanding the impact of ACh availability on vesicle filling and recycling.

scholarly journals Congenital Myasthenic Syndrome Due to Choline Acetyltransferase Mutations in Infants

2013 ◽  
Vol 29 (3) ◽  
pp. 389-393 ◽  
Author(s):  
Robertino Dilena ◽  
Angela Abicht ◽  
Paola Sergi ◽  
Giacomo P. Comi ◽  
Alessio Di Fonzo ◽  
...  
Keyword(s):  
Choline Acetyltransferase ◽  
Congenital Myasthenic Syndrome ◽  
Myasthenic Syndrome

Paternal Δ9-Tetrahydrocannabinol Exposure Prior to Mating Elicits Deficits in Cholinergic Synaptic Function in the Offspring

2020 ◽  
Vol 174 (2) ◽  
pp. 210-217
Author(s):  
Theodore A Slotkin ◽  
Samantha Skavicus ◽  
Edward D Levin ◽  
Frederic J Seidler
Keyword(s):  
Brain Development ◽  
Choline Acetyltransferase ◽  
Drug Exposure ◽  
Brain Regions ◽  
Synaptic Function ◽  
Male Rats ◽  
High Dose ◽  
Age Related ◽  
The Impact ◽  
Ach Receptors

Abstract Little attention has been paid to the potential impact of paternal marijuana use on offspring brain development. We administered Δ9-tetrahydrocannabinol (THC, 0, 2, or 4 mg/kg/day) to male rats for 28 days. Two days after the last THC treatment, the males were mated to drug-naïve females. We then assessed the impact on development of acetylcholine (ACh) systems in the offspring, encompassing the period from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), and including brain regions encompassing the majority of ACh terminals and cell bodies. Δ9-Tetrahydrocannabinol produced a dose-dependent deficit in hemicholinium-3 binding, an index of presynaptic ACh activity, superimposed on regionally selective increases in choline acetyltransferase activity, a biomarker for numbers of ACh terminals. The combined effects produced a persistent decrement in the hemicholinium-3/choline acetyltransferase ratio, an index of impulse activity per nerve terminal. At the low THC dose, the decreased presynaptic activity was partially compensated by upregulation of nicotinic ACh receptors, whereas at the high dose, receptors were subnormal, an effect that would exacerbate the presynaptic defect. Superimposed on these effects, either dose of THC also accelerated the age-related decline in nicotinic ACh receptors. Our studies provide evidence for adverse effects of paternal THC administration on neurodevelopment in the offspring and further demonstrate that adverse impacts of drug exposure on brain development are not limited to effects mediated by the embryonic or fetal chemical environment, but rather that vulnerability is engendered by exposures occurring prior to conception, involving the father as well as the mother.

Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase

2003 ◽  
Vol 13 (3) ◽  
pp. 245-251 ◽  
Author(s):  
Carolin Schmidt ◽  
Angela Abicht ◽  
Klaus Krampfl ◽  
Wolfgang Voss ◽  
Rolf Stucka ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Choline Acetyltransferase ◽  
Congenital Myasthenic Syndrome ◽  
Gene Encoding ◽  
Myasthenic Syndrome

scholarly journals Protein Kinase C Isoforms Differentially Phosphorylate Human Choline Acetyltransferase Regulating Its Catalytic Activity

2004 ◽  
Vol 279 (50) ◽  
pp. 52059-52068 ◽  
Author(s):  
Tomas Dobransky ◽  
Amanda Doherty-Kirby ◽  
Ae-Ri Kim ◽  
Dyanne Brewer ◽  
Gilles Lajoie ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Choline Acetyltransferase ◽  
Cholinergic Neurons ◽  
Congenital Myasthenic Syndrome ◽  
Chat Activity ◽  
Kinase C ◽  
Pkc Isoforms ◽  
Myasthenic Syndrome ◽  
Pkc Activation

Choline acetyltransferase (ChAT) synthesizes acetylcholine in cholinergic neurons; regulation of its activity or response to physiological stimuli is poorly understood. We show that ChAT is differentially phosphorylated by protein kinase C (PKC) isoforms on four serines (Ser-440, Ser-346, Ser-347, and Ser-476) and one threonine (Thr-255). This phosphorylation is hierarchical, with phosphorylation at Ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. Ser-476 with Ser-440 and Ser-346/347 maintains basal ChAT activity. Ser-440 is targeted by Arg-442 for phosphorylation by PKC. Arg-442 is mutated spontaneously (R442H) in congenital myasthenic syndrome, rendering ChAT inactive and causing neuromuscular failure. This mutation eliminates phosphorylation of Ser-440, and Arg-442, not phosphorylation of Ser-440, appears primarily responsible for ChAT activity, with Ser-440 phosphorylation modulating catalysis. Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity.

scholarly journals Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations

2015 ◽  
Vol 36 (9) ◽  
pp. 881-893 ◽  
Author(s):  
Juan Arredondo ◽  
Marian Lara ◽  
Sídney M. Gospe ◽  
Claudio G. Mazia ◽  
Maria Vaccarezza ◽  
...  
Keyword(s):  
Choline Acetyltransferase ◽  
Congenital Myasthenic Syndrome ◽  
Myasthenic Syndrome

scholarly journals COVID-19 in a Cohort of Patients with Congenital Myasthenic Syndrome

2021 ◽  
pp. 1-3
Author(s):  
Setareh Alabaf ◽  
Karen O'Connell ◽  
Sithara Ramdas ◽  
David Beeson ◽  
Jacqueline Palace
Keyword(s):  
High Risk ◽  
Neuromuscular Transmission ◽  
Genetic Disorders ◽  
Severe Disease ◽  
Congenital Myasthenic Syndrome ◽  
Referral Centre ◽  
History Of ◽  
Myasthenic Syndrome ◽  
The Uk ◽  
Rare Group

Congenital Myasthenic Syndrome (CMS) are a rare group of genetic disorders of neuromuscular transmission. Some subtypes of CMS can be associated with respiratory and bulbar weakness and these patients may therefore be at high risk of developing a severe disease from COVID-19. We screened 73 patients with genetically confirmed CMS who were attending the UK national referral centre for evidence of previous Severe Acute Respiratory Syndrome Corona Virus 2 infection and their clinical outcome. Of 73 patients, seven had history of confirmed COVID-19. None of the infected patients developed a severe disease, and there were no signals that CMS alone carries a high risk of severe disease from COVID-19.

scholarly journals Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

2021 ◽  
Vol 6 (2) ◽  
pp. 48
Author(s):  
Elisa Innocenzi ◽  
Ida Cariati ◽  
Emanuela De Domenico ◽  
Erika Tiberi ◽  
Giovanna D’Arcangelo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Aerobic Exercise ◽  
Frontal Cortex ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Brain Regions ◽  
Synaptic Function ◽  
Molecular Changes ◽  
Beneficial Effects ◽  
The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

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