The Leaner P/Q-type Calcium Channel Mutation Renders Cerebellar Purkinje Neurons Hyper-Excitable and Eliminates Ca2+-Na+ Spike Bursts

Eur J Neurosci. 2008 Jan;27(1):93-103. doi: 10.1111/j.1460-9568.2007.05998.x. Epub 2007 Dec 17.

Abstract

The leaner mouse mutation of the Cacna1a gene leads to a reduction in P-type Ca2+ current, the dominant Ca2+ current in Purkinje cells (PCs). Here, we compare the electro-responsiveness and structure of PCs from age-matched leaner and wild-type (WT) mice in pharmacological isolation from synaptic inputs in cerebellar slices. We report that compared with WT, leaner PCs exhibit lower current threshold for Na+ spike firing, larger subthreshold membrane depolarization, rapid adaptation followed by complete block of Na+ spikes upon strong depolarization, and fail to generate Ca2+-Na+ spike bursts. The Na+ spike waveforms in leaner PCs have slower kinetics, reduced spike amplitude and afterhyperpolarization. We show that a deficit in the P-type Ca2+ current caused by the leaner mutation accounts for most but not all of the changes in mutant PC electro-responsiveness. The selective P-type Ca2+ channel blocker, omega-agatoxin-IVA, eliminated differences in subthreshold membrane depolarization, adaptation of Na+ spikes upon strong current-pulse stimuli, Na+ spike waveforms and Ca2+-Na+ burst activity. In contrast, a lower current threshold for eliciting repetitive Na+ spikes in leaner PCs was still observed after blockade of the P-type Ca2+ current, suggesting secondary effects of the mutation that render PCs hyper-excitable. Higher input resistance, reduced whole-cell capacitance and smaller dendritic size accompanied the enhanced excitability in leaner PCs, indicative of developmental retardation in these cells caused by P/Q-type Ca2+ channel malfunction. Our data indicate that a deficit in P-type Ca2+ current leads to complex functional and structural changes in PCs, impairing their intrinsic and integrative properties.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology*
  • Action Potentials / radiation effects
  • Animals
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, Q-Type / deficiency
  • Calcium Channels, Q-Type / genetics*
  • Cerebellum / cytology*
  • Dose-Response Relationship, Radiation
  • Electric Stimulation / methods
  • In Vitro Techniques
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Mutation / genetics*
  • Patch-Clamp Techniques
  • Purkinje Cells / drug effects
  • Purkinje Cells / physiology*
  • Purkinje Cells / radiation effects
  • Sodium / metabolism
  • omega-Conotoxin GVIA / pharmacology

Substances

  • Calcium Channel Blockers
  • Calcium Channels, Q-Type
  • omega-Conotoxin GVIA
  • Sodium
  • Calcium