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Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking
K Jun1, E S Piedras-Rentería, S M Smith
1National Creative Research Initiatives Center for Calcium and Learning, Pohang University of Science and Technology, Pohang, Korea.
Abstract:
The Ca(2+) channel alpha(1A)-subunit is a voltage-gated, pore-forming membrane protein positioned at the intersection of two important lines of research: one exploring the diversity of Ca(2+) channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. alpha(1A)-Subunits are thought to support both P- and Q-type Ca(2+) channel currents, but the most direct test, a null mutant, has not been described, nor is it known which changes in neurotransmission might arise from elimination of the predominant Ca(2+) delivery system at excitatory nerve terminals. We generated alpha(1A)-deficient mice (alpha(1A)(-/-)) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying approximately 3-4 weeks after birth. P-type currents in Purkinje neurons and P- and Q-type currents in cerebellar granule cells were eliminated completely whereas other Ca(2+) channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in alpha(1A)(-/-) hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca(2+) entry. The alpha(1A)(-/-) mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in alpha(1A).
Insights
Calcium channel alpha(1A)-subunit deficiency causes neurological deficits in mice, impacting ataxia and dystonia. This study reveals critical roles for alpha(1A)-subunits in neuronal function and disease mechanisms.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The Ca(2+) channel alpha(1A)-subunit is crucial for neuronal function and implicated in neurological disorders.
- Its precise physiological roles and contribution to neurotransmission remain incompletely understood.
Purpose of the Study:
- To investigate the function of the Ca(2+) channel alpha(1A)-subunit by creating and analyzing alpha(1A)-deficient mice.
- To elucidate the impact of alpha(1A)-subunit elimination on Ca(2+) channel currents and synaptic transmission.
Main Methods:
- Generation of alpha(1A)-deficient (alpha(1A)(-/-)) mice.
- Electrophysiological recordings in Purkinje neurons and cerebellar granule cells.
- Analysis of synaptic transmission in hippocampal slices.
Main Results:
- Alpha(1A)(-/-) mice exhibited progressive ataxia and dystonia, succumbing within 3-4 weeks of birth.
- Complete elimination of P-type currents in Purkinje neurons and P/Q-type currents in cerebellar granule cells.
- Synaptic transmission in alpha(1A)(-/-) mice showed altered reliance on N-type and R-type Ca(2+) channels.
Conclusions:
- The Ca(2+) channel alpha(1A)-subunit is essential for normal neurological function and survival.
- Alpha(1A)-subunit deficiency profoundly affects specific Ca(2+) channel currents and synaptic transmission.
- These mice serve as a valuable model for studying human diseases linked to alpha(1A)-subunit mutations.