Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia

Abstract

In degenerative neurological disorders such as Parkinson’s disease, a convergence of widely varying insults results in a loss of dopaminergic neurons and, thus, the motor symptoms of the disease. Dopamine replacement therapy with agents such as levodopa is a mainstay of therapy. Cerebellar ataxias, a heterogeneous group of currently untreatable conditions, have not been identified to have a shared physiology that is a target of therapy. In this review, we propose that perturbations in cerebellar Purkinje neuron intrinsic membrane excitability, a result of ion channel dysregulation, is a common pathophysiologic mechanism that drives motor impairment and vulnerability to degeneration in cerebellar ataxias of widely differing genetic etiologies. We further propose that treatments aimed at restoring Purkinje neuron intrinsic membrane excitability have the potential to be a shared therapy in cerebellar ataxia akin to levodopa for Parkinson’s disease.

Nucleoporin Nup358 Downregulation Tunes the Neuronal Excitability in Mouse Cortical Neurons

“…Although they were obtained on non-pathological cell models, we hope that our findings might constitute seminal results towards the functional study of Nup-related defects, which will need future experiments. Succeeding in this, the electrical correlate of altered neuron membrane excitability due to ion channel dysregulation, as already effectively proposed as a putative target/marker of the disease [ 18 , 19 , 20 , 37 ], could be extended at the NPC-Nup-NCT machinery level. Accordingly, our future goals will comprise the developing of ion channel-targeted neurotherapies based on the Nup pathogenetic cascade, according to modern pharmacogenetics and personalized pharmacology guidelines [ 38 , 39 ] established for neurological disorders.…”

Oxidative stress and ion channels in neurodegenerative diseases

“…Various neurodegenerative disorders are believed to be impacted by oxidative stress ( Figure 1 ). Ion channels’ dysregulation is another common pathophysiologic mechanism that causes degenerative CNS diseases of widely differing genetic etiologies ( Huang and Shakkottai, 2023 ). Furthermore, H 2 S at low concentrations lowers the level of ROS and thus protects neurons from oxidative stresses ( Shefa et al, 2018 ).…”

“…A cerebellar cortex includes Purkinje cells that integrate all input into the cerebellum ( Hosy et al, 2011 ; Hirano, 2018 ; Huang and Shakkottai, 2023 ). A common feature of cerebellar ataxia is cerebellar atrophy and Purkinje neuron degeneration ( Koeppen, 2005 ; Cocozza et al, 2021 ).…”

“…In resting conditions, Purkinje neurons fire at an average frequency of 40 Hz with unvarying inter-spike interval duration. Ion channels are predominantly responsible for maintaining this regularity ( Raman and Bean, 1999 ; Braga Neto et al, 2016 ; Huang and Shakkottai, 2023 ).…”

The Role of Cerebellar Intrinsic Neuronal Excitability, Synaptic Plasticity, and Perineuronal Nets in Eyeblink Conditioning

“…A substantial amount of work has been performed to understand changes in intrinsic membrane excitability—changes in the likelihood of generating an action potential—and how these changes are involved in eyeblink conditioning. Changes in intrinsic membrane excitability are changes in the movement of ions across the membrane and come about by the insertion, removal, or modification of sodium, calcium, potassium, or non-selective cation channels [ 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. These changes can occur as an increase or decrease in input resistance, membrane potential, afterhyperpolarization, spike threshold, spike frequency, or a combination of these properties.…”