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bioRxiv · 10.1101/2023.11.29.569172

Ionic conductances driving tonic firing in Purkinje neurons of larval zebrafish

Jadhav, M. P.·Thirumalai, V.
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Abstract

Purkinje neurons are critical for the functioning of the cerebellum, which is among the oldest and most conserved regions of the vertebrate brain. In mammals and in larval zebrafish, Purkinje neurons can generate tonic firing even when isolated from the network. Here we investigated the ionic basis of tonic firing in Purkinje neurons of larval zebrafish using voltage clamp for isolation of membrane currents along with pharmacology. We discovered that these neurons express L-type and P/Q-type high voltage-gated calcium currents, T-type low voltage-gated calcium currents and SK and BK-type calcium dependent potassium currents. Among these, L-type calcium currents and SK-type calcium-dependent potassium currents were indispensable for tonic firing, while blocking T-type, P/Q-type and BK currents had little effect in comparison. We observed that action potentials were broadened when either L-type or SK channels were blocked. Based on these results, we propose that calcium entry via L-type calcium channels activates SK potassium channels leading to faster action potential repolarization, in turn aiding the removal of inactivation of sodium channels. This allows larval zebrafish Purkinje neurons to continue to fire tonically for sustained periods. In mammals also, tonic firing in Purkinje neurons is driven by calcium channels coupling to calcium-dependent potassium channels, yet the specific types of channels involved are different. We therefore suggest that coupling of calcium channels and calcium-dependent potassium channels could be a conserved mechanism for sustaining long bouts of high frequency firing. Key pointsO_LITonic firing is an intrinsic property of Purkinje neurons in mammals and fish. C_LIO_LIThese neurons express multiple types of voltage-gated conductances including L-type, T-type, and P/Q-type calcium currents and SK- and BK-type calcium-dependent potassium currents. C_LIO_LIBlocking L-type calcium channels and SK-type calcium dependent potassium channels resulted in spike broadening and reduced tonic firing. C_LIO_LIL-type calcium currents were activated during the repolarization of the spike. C_LIO_LIBased on this we conclude that calcium entry via L-type channels activates SK-channels causing faster repolarization of the spike and therefore sustained tonic firing. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/569172v3_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@4ac7a5org.highwire.dtl.DTLVardef@1792e18org.highwire.dtl.DTLVardef@c1557forg.highwire.dtl.DTLVardef@d4084f_HPS_FORMAT_FIGEXP M_FIG C_FIG Legend: Top: The activation of voltage gated sodium channels (INa, pink), voltage gated calcium channels (ICa, dotted green), and SK-type channels (ISK, teal) during the action potential (Vm, black). Bottom: Under control conditions, sodium entry via voltage-gated sodium channels leads to depolarisation resulting in the activation of calcium channels. The elevation of intracellular calcium levels activates SK-type calcium-dependent potassium channels which repolarise the membrane, removing sodium channel inactivation. With L-type voltage-gated calcium channels blocked, this process is affected causing cessation of sustained tonic spiking.

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Jadhav, M. P., Thirumalai, V.. 2023-12-01. Ionic conductances driving tonic firing in Purkinje neurons of larval zebrafish. https://doi.org/10.1101/2023.11.29.569172

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