T-type calcium channels mediate rebound firing in intact deep cerebellar neurons.
Neurons of the deep cerebellar nuclei (DCN) form the main output of the cerebellar circuitry and thus play an important role in cerebellar motor coordination. A prominent biophysical property observed in rat DCN neurons is rebound firing; a brief but strong hyperpolarizing input transiently increases their firing rate to much higher levels compared with that prior to the inhibitory input. Low-threshold T-type voltage-gated calcium channels have been suspected for a long time to be responsible for this phenomenon, but direct pharmacological evidence in support of this proposition is lacking. Even though a multitude of functional roles has been assigned to rebound firing in DCN neurons, their prevalence under physiological conditions is in question. Studies aimed at delineating the physiological role of rebound firing are hampered by the lack of a good pharmacological blocker. Here we show that mibefradil, a compound that blocks T-type calcium channels, potently blocks rebound firing in DCN neurons. In whole-cell experiments both mibefradil and NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride]. a more selective T-type calcium channel blocker, effectively blocked rebound firing produced by direct current injection. Thus, mibefradil and other T-type channel modulators may prove to be invaluable tools for elucidating the functional importance of DCN rebound firing in cerebellar computation.
Alviña
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Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Kennedy Center Room 506, Bronx, NY 10461, USA.
Ellis-Davies
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G
Khodakhah
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D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000502:physiology*; D002531:Cerebellum / Q000166:cytology*; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D066298:In Vitro Techniques; D020748:Mibefradil / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D020748:Mibefradil; D005680:gamma-Aminobutyric Acid