Abstract
The Purkinje cell (PC) is among the most complex neurons in the brain and plays a critical role for cerebellar functioning. PCs operate as fast pacemakers modulated by synaptic inputs but can switch from simple spikes to complex bursts and, in some conditions, show bistability. In contrast to original works emphasizing dendritic Ca-dependent mechanisms, recent experiments have supported a primary role for axonal Na-dependent processing, which could effectively regulate spike generation and transmission to deep cerebellar nuclei (DCN). In order to account for the numerous ionic mechanisms involved (at present including Nav1.6, Cav2.1, Cav3.1, Cav3.2, Cav3.3, Kv1.1, Kv1.5, Kv3.3, Kv3.4, Kv4.3, KCa1.1, KCa2.2, KCa3.1, Kir2.x, HCN1), we have elaborated a multicompartmental model incorporating available knowledge on localization and gating of PC ionic channels. The axon, including initial segment (AIS) and Ranvier nodes (RNs), proved critical to obtain appropriate pacemaking and firing frequency modulation. Simple spikes initiated in the AIS and protracted discharges were stabilized in the soma through Na-dependent mechanisms, while somato-dendritic Ca channels contributed to sustain pacemaking and to generate complex bursting at high discharge regimes. Bistability occurred only following Na and Ca channel down-regulation. In addition, specific properties in RNs K currents were required to limit spike transmission frequency along the axon. The model showed how organized electroresponsive functions could emerge from the molecular complexity of PCs and showed that the axon is fundamental to complement ionic channel compartmentalization enabling action potential processing and transmission of specific spike patterns to DCN.
Highlights
Neurons are the most complex cells, from a biochemical and biophysical point of view, of the entire human body
The model consisted of a somatic compartment, of 1599 dendritic compartments divided into three orders of branches, and of an axon made by axon initial segment (AIS), paraAIS, three Ranvier nodes (RNs), four myelinated internodes and a two-compartment axonal collateral (Figure 1A; Table 1)
SUMMARY AND CONCLUSIONS Since the model quantitatively reproduced simple firing as well as complex bursting and axonal spike propagation, available physiological knowledge proved sufficient to explain the fundamental aspects of Purkinje cell (PC) electroresponsiveness
Summary
Neurons are the most complex cells, from a biochemical and biophysical point of view, of the entire human body. Neuronal functions critically depend on their ionic channels, expressed in different subtypes and selectively distributed in different cell sections, and on an intricate network of intracellular regulatory systems (Koch, 1999). A prototypical case of neuronal complexity is the Purkinje cell (PC) of the cerebellum. Discovered in the 19th century by Jan Evangelista Purkinje (Zárskı, 2012) this neuron was described by Golgi and Cajal (De Carlos and Borrell, 2007) and deeply investigated in seminal works (Eccles et al, 1966; Llinas and Sugimori, 1980a). New critical functional features and molecular properties have been discovered since and the biophysical mechanisms of PC electroresponsiveness need to be reassessed
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