Motor dysfunction and altered synaptic transmission at the parallel fiber-Purkinje cell synapse in mice lacking potassium channels Kv3.1 and Kv3.3.
Micelacking both Kv3.1 and both Kv3.3 K+ channel alleles display severe motor deficits such as tremor, myoclonus, and ataxic gait. Micelacking one to three alleles at the Kv3.1 and Kv3.3 loci exhibit in an allele dose-dependent manner a modest degree of ataxia. Cerebellar granule cells coexpress Kv3.1 and Kv3.3 K+ channels and are therefore candidate neurons that might be involved in these behavioral deficits. Hence, we investigated the synaptic mechanisms of transmission in the parallel fiber-Purkinje cell system. Action potentials of parallel fibers were broader in mice lacking both Kv3.1 and both Kv3.3 alleles and in mice lacking both Kv3.1 and a single Kv3.3 allele compared with those of wild-type mice. The transmission of high-frequency trains of action potentials was only impaired at 200 Hz but not at 100 Hz in mice lacking both Kv3.1 and Kv3.3 genes. However, paired-pulse facilitation (PPF) at parallel fiber-Purkinje cell synapses was dramatically reduced in a gene dose-dependent manner in mice lacking Kv3.1 or Kv3.3 alleles. Normal PPF could be restored by reducing the extracellular Ca2+ concentration indicating that increased activity-dependent presynaptic Ca2+ influx, at least in part caused the altered PPF in mutant mice. Induction of metabotropic glutamate receptor-mediated EPSCs was facilitated, whereas longterm depression was not impaired but rather facilitated in Kv3.1/Kv3.3 double-knockout mice. These results demonstrate the importance of Kv3 potassium channels in regulating the dynamics of synaptic transmission at the parallel fiber-Purkinje cell synapse and suggest a correlation between short-term plasticity at the parallel fiber-Purkinje cell synapse and motor performance.
Matsukawa
Hiroshi
H
Laboratory for Neuronal Circuit Dynamics, RIKEN Brain Science Institute, Wako, Japan 351-0198.
Wolf
Alexander M
AM
Matsushita
Shinichi
S
Joho
Rolf H
RH
Knöpfel
Thomas
T
D000200:Action Potentials; D000818:Animals; D001259:Ataxia / Q000209:etiology; D001522:Behavior, Animal; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000503:physiopathology*; D020820:Dyskinesias / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D036881:Long-Term Synaptic Depression; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009412:Nerve Fibers / Q000502:physiology; D009473:Neuronal Plasticity; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011689:Purkinje Cells / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D051670:Shaw Potassium Channels; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission
C085724:Kcnc3 protein, mouse; D009479:Neuropeptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D018094:Receptors, Metabotropic Glutamate; D051670:Shaw Potassium Channels; C104077:metabotropic glutamate receptor type 1; D002118:Calcium