Introduction

Neurons are electrically excitable cells that respond to input signals by generating electrical impulses propagated as action potentials throughout the cell and its axon. Action potentials arise from changes in the cationic gradient, primarily sodium and potassium, across the plasma membrane. Action potentials ultimately reach the axonal terminal and depolarize neighboring cells through synapses. Neuronal interaction occurs at synapses through synaptic transmission.[1]

Under resting conditions, the intracellular environment remains negative relative to the extracellular space. This electrical state represents the resting membrane potential, approximately −60 mV. Generation of a neuronal action potential occurs when the membrane potential becomes less negative and reaches the threshold. The resulting change in membrane potential opens voltage-gated sodium channels, initiating depolarization and action potential generation.

Neuronal action potentials enable impulse propagation along nerve fibers, even across long distances. Action potentials also mediate communication among neurons through synapses. Disruption of this mechanism can produce severe consequences, including failure of impulse generation and conduction, as observed with various neurotoxins and demyelinating disorders.[2]

Structure and Function

The neuronal membrane potential arises from differences in the concentration of charged ions across the cellular membrane. The lipid bilayer of the neuronal membrane functions as a capacitor, whereas transmembrane ion channels function as resistors. This resting (steady-state) potential is essential for neuronal physiological stability. Maintenance of the resting membrane potential depends on unequal ionic distribution across the cellular membrane, established by pumps driven by adenosine triphosphate (ATP), most notably sodium–potassium antiporters. These exchangers pump sodium from the intracellular space into the extracellular compartment and potassium into the intracellular compartment.[3]

The opening of ion channels permits permeable ions to flow down electrochemical gradients, thereby altering the membrane potential. Channel gating occurs through 2nd messengers, neurotransmitters, or changes in membrane voltage. Voltage-gated cation channels serve as the principal channels involved in the generation and propagation of neuronal action potentials.

The human brain contains approximately 100 billion neurons and about a quadrillion synapses (see Image. Anatomy of Neurons).[4][5] Each neuron forms roughly 1,000 synapses on average, influencing the electrical potential of the membrane. Depolarization occurs when the resting membrane potential (−60 mV) becomes less negative. Hyperrpolarization results when the membrane potential becomes more negative. Integration of ionic movements, particularly sodium influx, may provide adequate depolarizing input to reach the threshold potential. Achievement of the threshold requires entry of sufficient positively charged ions into the cell, thereby terminating membrane polarity in a process termed "depolarization."

At normal body temperature, the equilibrium potential is approximately +55 mV for sodium and −103 mV for potassium. Three stages characterize the generation of the action potential, as follows (see Image. Action Potential Phases):

1. Depolarization, which changes the membrane potential from −60 mV to +40 mV and is primarily caused by sodium influx
2. Repolarization, a return toward the resting membrane potential primarily caused by potassium efflux
3. Afterhyperpolarization, representing recovery from a slight overshoot of repolarization [6]

Stage 1 is governed by increased membrane permeability to sodium. Removal of extracellular sodium or inactivation of sodium channels prevents action potential generation.[7] An action potential renders the neuron incapable of immediately generating a subsequent one. This interval constitutes the absolute refractory period, during which sodium channels remain inactivated and closed, while potassium channels remain open. The ARP is followed by the relative refractory period, during which initiation of an action potential requires a substantially higher threshold. Partial recovery of sodium channels and continued opening of some potassium channels characterize this phase (see Image. Ionic Channel Activity During Action Potentials). The duration of these refractory periods determines the rate at which action potentials can be generated and propagated.

Propagation of the action potential continues until termination at a synapse. Arrival of the action potential may trigger neurotransmitter release or activate ionic currents. Ionic current transmission occurs at electrical synapses, where presynaptic and postsynaptic cells connect directly without neurotransmitters.[8] However, neurotransmitter-mediated signaling predominates and is observed at chemical synapses and neuromuscular junctions.[9]

Local currents generated by depolarization along a portion of the neuronal membrane can, if sufficiently strong, depolarize neighboring membrane segments to threshold. This process propagates the action potential along the membrane and down the neuron’s axon.

The primary factor determining propagation speed is the extent to which the initial local currents spread before inducing further depolarizations. Factors influencing this speed include the membrane’s electrical resistance and the internal composition of the axon.[10] Wider axons exhibit lower internal resistance. A higher density of voltage-gated sodium channels in the membrane decreases membrane resistance. Increased internal resistance and decreased membrane resistance both slow action potential propagation.

Physical constraints within the body limit axon size. To maximize propagation velocity, the nervous system employs glial cells, specifically oligodendrocytes and Schwann cells, to wrap around axons, forming myelin sheaths.[11] These sheaths increase membrane resistance and reduce current leakage at areas that would otherwise permit ionic loss.

Despite myelination, action potentials can only propagate a finite distance before additional sodium channels are required to maintain depolarization. Gaps in the myelin sheath, called "nodes of Ranvier," contain high concentrations of voltage-gated sodium channels. These nodes regenerate the action potential along the axon in a process termed "saltatory conduction."[12]

Clinical Significance

The rapid depolarization, or upstroke, of the neuronal action potential results from the opening of voltage-gated sodium channels.[13] These channels are large transmembrane proteins composed of distinct subunits encoded by 10 mammalian genes.[14] Dysfunction of these channels is collectively termed "channelopathies."[15] Channelopathies affect excitable tissues, including neurons, skeletal muscle, and cardiac muscle, producing a variety of diseases. Neurological channelopathies can affect both neuronal and skeletal muscle tissues. Paramyotonia congenita arises from mutations in the gene encoding the α1 subunit of the sodium channel. Sodium channelopathies in the brain contribute to multiple forms of refractory epilepsy.

A variety of neurotoxins can block the action potential.[16][17] A particularly potent toxin is tetrodotoxin (TTX), which inhibits sodium channels.[18] This naturally occurring toxin is typically ingested orally from pufferfish, a component of Japanese cuisine. The occurrence of TTX has spread beyond Southeast Asia to the Pacific and Mediterranean regions and has been identified in multiple other species.

TTX binds to and inactivates sodium channels, rendering affected tissues immobile and insensitive. Symptom onset and severity correlate with the amount ingested. Early manifestations often include paraesthesias of the tongue and lips, which may be accompanied or followed by headache and vomiting. Progressive symptoms include muscle weakness, ataxia, diarrhea, dizziness, and loss of reflexes. Death may result from respiratory or cardiac failure.

Of clinical interest, TTX exhibits some analgesic activity and has been investigated for pain management. Low doses may also reduce heroin craving. No definitive cure exists, and TTX poisoning is frequently fatal. Treatment is primarily supportive. Respiratory compromise is managed with endotracheal intubation or mechanical ventilation. Early stages of poisoning may be managed with activated charcoal to adsorb the toxin prior to gastric absorption, as well as gastric lavage to reduce symptom severity.[19]

Ciguatoxin is a potent marine neurotoxin that activates voltage-gated sodium channels, causing persistent depolarization. Exposure induces rapid-onset numbness, paraesthesia, dysaesthesia, and muscle paralysis. The toxin is produced by dinoflagellates. Human exposure occurs through ingestion of carnivorous coral reef fishes, including grouper, red snapper, and barracuda, which accumulate the toxin by feeding on fish that have consumed the dinoflagellates.

Saxitoxin and its derivatives, collectively known as paralytic shellfish toxins (PSTs), are produced by dinoflagellates in marine and freshwater environments. PSTs block voltage-gated sodium channels, preventing sodium influx and inhibiting membrane depolarization. Some PSTs may have limited effects on other ion channels, including potassium and calcium channels. Mechanistic similarity to TTX underlies the comparable clinical effects of PST exposure. Severe toxicity can result in profound hypotension and generalized paralysis, and death may occur from respiratory failure or hypotension.[20][21]

The impact of myelin on saltatory conduction is demonstrated by demyelinating diseases, which slow action potential propagation to varying degrees.[22] Multiple sclerosis destroys oligodendrocytes, which maintain the fatty layer of the myelin sheath and support efficient electrical signal propagation.[23] Progressive myelin loss eventually leads to the breakdown of neuronal axons.[24]

Multiple sclerosis commonly presents in young women and produces a wide range of physical, cognitive, and psychiatric manifestations, including diplopia, blindness, muscle weakness, speech impairment, tremors, incontinence, and vertigo. Diagnosis may be supported by the detection of oligoclonal bands of immunoglobulin G in cerebrospinal fluid via electrophoresis, which are present in many patients with multiple sclerosis.[25][26][27][28]

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Disclosure: Felix Jozsa declares no relevant financial relationships with ineligible companies.

Disclosure: Forshing Lui declares no relevant financial relationships with ineligible companies.