FHF-independent conduction of action potentials along the leak-resistant cerebellar granule cell axon

Abstract

Neurons in vertebrate central nervous systems initiate and conduct sodium action potentials in distinct subcellular compartments that differ architecturally and electrically. Here, we report several unanticipated passive and active properties of the cerebellar granule cell's unmyelinated axon. Whereas spike initiation at the axon initial segment relies on sodium channel (Na v )-associated fibroblast growth factor homologous factor (FHF) proteins to delay Na v inactivation, distal axonal Na v s show little FHF association or FHF requirement for high-frequency transmission, velocity and waveforms of conducting action potentials. In addition, leak conductance density along the distal axon is estimated as o1% that of somatodendritic membrane. The faster inactivation rate of FHF-free Na v s together with very low axonal leak conductance serves to minimize ionic fluxes and energetic demand during repetitive spike conduction and at rest. The absence of FHFs from Na v s at nodes of Ranvier in the central nervous system suggests a similar mechanism of current flux minimization along myelinated axons.

Parameter tuning differentiates granule cell subtypes enriching the repertoire of retransmission properties at the cerebellum input stage

“…The GrC model used in this study was written in Python 2.7/NEURON 7.6 (Hines and Carnevale, 2001;Hines et al, 2009). The model derived from previous ones (D'Angelo et al, 2001;Nieus et al, 2006;Diwakar et al, 2009) and was upgraded to account for advanced mechanisms of spike generation and conduction in the axon (Dover et al, 2016). The ionic channels were distributed among dendrites, soma, hillock, axonal initial segment (AIS), ascending axon (AA) and parallel fibers (PF) (Masoli et al, 2017).…”

“…The electrotonic structure of the granule cell models was derived from (Dover et al, 2016) along with passive parameters ( Table 1 in Supplemental Material). The GrC ionic channel models and distributions were taken from previous papers and updated according to the latest literature when needed (Table 2 in Supplemental Material).…”

“…A model was discarded when (1) spike generation in the AIS failed, (2) spike conduction speed or spike amplitude in the AA and PFs was decremental, (3) spike frequency was different in soma and axon (>± 1 spike/sec) (e.g. see (Dover et al, 2016)).…”

“…Since it is experimentally unpractical to determine the balance of multiple ionic conductances in single GrCs, we inferred membrane mechanisms from simulations using biophysically detailed data-driven models (Fig. 5A) (D'Angelo et al, 2001;Nieus et al, 2006;Diwakar et al, 2009;Dover et al, 2016;Masoli et al, 2017) incorporating multiple types of ionic channels on the dendrites, soma, hillock, axonal initial segment, ascending axon and parallel fibers ( Fig. 5B; see also Supplemental Fig.…”

“…Later on, electrophysiological recordings from the cerebellar vermis of rodents reported a stereotyped firing pattern with spikes organized in regular discharges with little or no adaptation (D'Angelo et al, 1995;Brickley et al, 1996;Cathala et al, 2003). The experimental identification of a basic set of 8 ionic mechanisms allowed to model GrC firing in great detail (D'Angelo et al, 2001;Goldfarb et al, 2007;Diwakar et al, 2009;Dover et al, 2016) leading to a "canonical" description of GrCs but the question about the potential differentiation of firing properties remained open.…”