Brain channelopathies are a group of neurological disorders that result from genetic mutations affecting ion channels in the brain. Ion channels are specialized proteins that play a crucial role in the electrical activity of nerve cells by controlling the flow of ions such as sodium, potassium, and calcium. When these channels are not functioning properly, they can cause a wide range of neurological symptoms such as seizures, movement disorders, and cognitive impairment. In this context, the axon initial segment (AIS) is the site of action potential initiation in most neurons. This region is characterized by a high density of voltage-gated sodium channels (VGSCs), which are responsible for the rapid depolarization that occurs when the neuron is stimulated. The AIS is also enriched in other ion channels, such as potassium channels, that play a role in shaping the action potential waveform and determining the firing frequency of the neuron. In addition to ion channels, the AIS contains a complex cytoskeletal structure that helps to anchor the channels in place and regulate their function. Therefore, alterations in this complex structure of ion channels, scaffold proteins, and specialized cytoskeleton may also cause brain channelopathies not necessarily associated with ion channel mutations. This review will focus on how the AISs structure, plasticity, and composition alterations may generate changes in action potentials and neuronal dysfunction leading to brain diseases. AIS function alterations may be the consequence of voltage-gated ion channel mutations, but also may be due to ligand-activated channels and receptors and AIS structural and membrane proteins that support the function of voltage-gated ion channels.
Keywords: axon initial segment; brain disease; voltage-gated ion channels.