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Voltage-dependent P/Q-type calcium channel subunit alpha-1A (Brain calcium channel I) (BI) (Calcium channel, L type, alpha-1 polypeptide isoform 4) (Voltage-gated calcium channel subunit alpha Cav2.1) [CACH4] [CACN3] [CACNL1A4]


Gene dosage-dependent transmitter release changes at neuromuscular synapses of CACNA1A R192Q knockin mice are non-progressive and do not lead to morphological changes or muscle weakness.

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.

MeSH Terms

  • Acetylcholine
  • Aging
  • Animals
  • Apoptosis
  • Bungarotoxins
  • Calcium Channels, N-Type
  • Calcium Channels, P-Type
  • Calcium Channels, Q-Type
  • Coloring Agents
  • Electric Stimulation
  • Electromyography
  • Electrophysiology
  • Gene Dosage
  • Hand Strength
  • Humans
  • Image Processing, Computer-Assisted
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Muscle Contraction
  • Muscle Weakness
  • Neuromuscular Junction
  • Neurotransmitter Agents
  • Synapses
  • Synaptic Transmission

Eye movements of the murine P/Q calcium channel mutant rocker, and the impact of aging.

Mutations in the gene encoding the ion pore of the P/Q voltage-activated calcium channel (CACNA1A) are predicted to alter synaptic transmission and dendritic excitability within cerebellar granule and Purkinje cells. Determining the relationships between these alterations, neuronal activity, and behavior may yield insight into the relationship between neuronal intrinsic properties and signal processing within the ocular motor system. Toward this end, we compared ocular motor performance in the CACNA1A mutant rocker and C57BL/6 controls. Average vertical eye position was abnormally elevated in the mutants, a finding that may be analogous to downbeat nystagmus seen in human cerebellar disorders. Fast phases of vestibular nystagmus were slowed by approximately 18% of control values. The angular vestibuloocular reflex (VOR) in darkness and light (visual VOR, or VVOR), assessed at 0.1-1.6 Hz, exhibited subnormal gains at the highest stimulus frequencies and increased phase leads at the lowest stimulus frequencies. Horizontal optokinetic responses to constant velocity drum rotation of /-2.5-40 degrees/s exhibited minimally reduced gains. Attempts to increase VOR gain by concomitant optokinetic and vestibular stimulation were confounded by the tendency of the mice to habituate to repetitive vestibular stimulation, but attempts to induce coupling of vertical eye movements to horizontal vestibular stimulation (cross-axis adaptation) generated rapid plastic changes in controls and little effect in mutants. With the notable exceptions of the vertical elevation and optokinetic gains, the ocular motor abnormalities were stable over a broad range of animal age, a result compatible with the abnormalities arising as direct consequences of the inborn alteration in calcium channel biophysics.

MeSH Terms

  • Adaptation, Physiological
  • Aging
  • Algorithms
  • Animals
  • Calcium Channels, P-Type
  • Calcium Channels, Q-Type
  • Calibration
  • Cerebellar Ataxia
  • Cerebellum
  • Darkness
  • Electrophysiology
  • Eye Movements
  • Kinetics
  • Light
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Neurons
  • Nystagmus, Physiologic
  • Ocular Motility Disorders
  • Phenotype
  • Reflex, Vestibulo-Ocular