Abstract:
:Ca(v)2.1 channels mediate neurotransmitter release at the neuromuscular junction (NMJ) and at many central synapses. Mutations in the encoding gene, CACNA1A, are thus likely to affect neurotransmitter release. Previously, we generated mice carrying the R192Q mutation, associated with human familial hemiplegic migraine type-1, and showed first evidence of enhanced presynaptic Ca(2+) influx [Neuron 41 (2004) 701]. Here, we characterize transmitter release in detail at mouse R192Q NMJs, including possible gene-dosage dependency, progression of changes with age, and associated morphological damage and muscle weakness. We found, at low Ca(2+), decreased paired-pulse facilitation of evoked acetylcholine release, elevated release probability, and increased size of the readily releasable transmitter vesicle pool. Spontaneous release was increased over a broad range of Ca(2+) concentrations (0.2-5mM). Upon high-rate nerve stimulation we observed some extra rundown of transmitter release. However, no clinical evidence of transmission block or muscle weakness was found, assessed with electromyography, grip-strength testing and muscle contraction experiments. We studied both adult ( approximately 3-6 months-old) and aged ( approximately 21-26 months-old) R192Q knockin mice to assess effects of chronic elevation of presynaptic Ca(2+) influx, but found no additional or progressive alterations. No changes in NMJ size or relevant ultrastructural parameters were found, at either age. Our characterizations strengthen the hypothesis of increased Ca(2+) flux through R192Q-mutated presynaptic Ca(v)2.1 channels and show that the resulting altered neurotransmitter release is not associated with morphological changes at the NMJ or muscle weakness, not even in the longer term.
journal_name
Neurosciencejournal_title
Neuroscienceauthors
Kaja S,van de Ven RC,Broos LA,Veldman H,van Dijk JG,Verschuuren JJ,Frants RR,Ferrari MD,van den Maagdenberg AM,Plomp JJdoi
10.1016/j.neuroscience.2005.04.069keywords:
subject
Has Abstractpub_date
2005-01-01 00:00:00pages
81-95issue
1eissn
0306-4522issn
1873-7544pii
S0306-4522(05)00462-8journal_volume
135pub_type
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