A CaV2.1 calcium channel mutation rocker reduces the number of postsynaptic AMPA receptors in parallel fiber-Purkinje cell synapses.
The rocker mice are hereditary ataxic mutants that carry a point mutation in the gene encoding the CaV2.1 (P/Q-type) Ca2+ channel alpha1 subunit, and show the mildest symptoms among the reported CaV2.1 mutant mice. We studied the basic characteristics of the rocker mutant Ca2+ channel and their impacts on excitatory synaptic transmission in cerebellar Purkinje cells (PCs). In acutely dissociated PC somas, the rocker mutant channel showed a moderate reduction in Ca2+ channel current density, whereas its kinetics and voltage dependency of gating remained nearly normal. Despite the small changes in channel function, synaptic transmission in the parallel fiber (PF)-PC synapses was severely impaired. The climbing fiber inputs onto PCs showed a moderate impairment but could elicit normal complex spikes. Presynaptic function of the PF-PC synapses, however, was unexpectedly almost normal in terms of paired-pulse facilitation, sensitivity to extracellular Ca2+ concentration and glutamate concentration in synaptic clefts. Electron microscopic analyses including freeze-fracture replica labeling revealed that both the number and density of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors substantially decreased without gross structural changes of the PF-PC synapses. We also observed an abnormal arborization of PC dendrites in young adult rocker mice (approximately 1 month old). These lines of evidence suggest that even a moderate dysfunction of CaV2.1 Ca2+ channel can cause substantial changes in postsynaptic molecular composition of the PF-PC synapses and dendritic structure of PCs.
Kodama
Takashi
T
Department of Information Physiology, National Institute for Physiological Sciences, Okazaki 444-8787, Japan.
Itsukaichi-Nishida
Yuko
Y
Fukazawa
Yugo
Y
Wakamori
Minoru
M
Miyata
Mariko
M
Molnar
Elek
E
Mori
Yasuo
Y
Shigemoto
Ryuichi
R
Imoto
Keiji
K
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002525:Cerebellar Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002526:Cerebellar Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D015640:Ion Channel Gating / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009154:Mutation / Q000235:genetics*; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission / Q000235:genetics
D002118:Calcium; D020864:Calcium Channels, N-Type; D018698:Glutamic Acid; D018091:Receptors, AMPA