Pathophysiology of Multiple Sclerosis: Action Potentials

This essay delves into the critical role of action potentials in the central nervous system (CNS) and their disruption in multiple sclerosis (MS). It explains how myelinated axons, with their myelin sheath and nodes of Ranvier, facilitate rapid electrical impulse transmission. The essay highlights the importance of the myelin sheath for efficient axonal conduction and the consequences of its damage. In MS, demyelination, inflammation, and lesions disrupt this process, leading to impaired action potential propagation. The text describes the molecular organization of the node of Ranvier and how its dysfunction contributes to the disease's pathophysiology. The essay explains how the loss of the myelin sheath leads to depolarization and exceeding the cell's safety margin. The conclusion underscores the impact of these disruptions on cognitive functions and the overall physiological health of the brain. The essay references several scientific publications to support its claims.

Action potentials along the myelin sheath and node of Ranvier: Pathophysiology of
multiple sclerosis
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Action potentials along the myelin sheath and node of Ranvier: Pathophysiology of
Multiple Sclerosis
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Action potentials along the myelin sheath and node of Ranvier: Pathophysiology of
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Introduction:
The axon in the central nervous system (CNS) is typically a neuronal process of considerable
length [1]. The primary function of this process of neuronal origin is to conduct electrical
impulses or ‘action potentials’ carrying information to the nerve ending/ terminal from the body
of the cell [1]. In the peripheral and central nervous systems (PNS and CNS respectively), there
are essentially two types of axons present: myelinated and unmyelinated i.e. containing a myelin
sheath or not containing it [1]. The myelinated axons are further composed of three segments: i)
summation point of somatic inputs in an initial segment where the action potential is generated;
ii) a second segment which effectively transmits the action potential in pulses of action potential
chain and it is usually of variable length; iii) The final segment is the preterminal end of the axon
leading to the region beyond where the expansion of the synaptic terminal occurs [1]. The
initiation of the action potential does not occur solely in the first composite segment of the axon
but also occurs in the second segment where the reliable transmission of the action potential
occurs [1]. There is absence of attenuation in the second segment of the myelinated axon [1, 2].
For the correct functioning of the CNS and the PNS, it is crucial that there is an efficient transfer
of information in the axons in the form of action potentials [2]. Research has indicated that
myelination is largely responsible for the increase in the speed of axonal conduction [2]. The
myelin sheath present on the axon allows for the rapid transmission of action potential to the
nerve terminal from the cell body [2]. The increased speed of axonal conduction ensures
enhanced efficiency of cognitive functionality [2]. Axonal conduction velocity, when accurately
regulated, leads to an improved coordination of motor neuronal skills and integration of sensory
perceptions and functionality [2]. Most neuropathologies thus conversely reflect the disruption

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and dysfunction in two primary specialised structures of axons that are vital for rapid axonal
conduction: a) the myelin sheath and b) the node of Ranvier [2]. The disruption of these two vital
structures of the axon leads to alterations in sensory perception, output of motor skills, and
cognitive processing [2]. Literature has several instances where the dysfunction of the node of
Ranvier is indicated as a crucial factor in the pathogenesis of most neurological disorders [2].
Myelin sheath and the node of Ranvier: role in axonal propogation of
action potentials:
In vertebrates, the rapid transmission of electrical impulses occurs across considerably large
distances [2]. Such transmission occurs through myelinated axons via the process of ‘saltatory
conduction’. The speed of conduction is higher in axons which are covered by a myelin sheath
[2, 3]. The myelin sheath is produced in the PNS by Schwann cells and oligodendrocytic cells in
the CNS [2, 3]. The myelin sheath is rich in lipids and is a multilayered structure [2]. The
effective resistance present in the axonal membrane is increased by the myelin sheath by
increasing the length of the electrical space constant and in turn increasing the speed of the
signals across the axon [2, 3]. Consequently, the effective capacitance value of the membrane of
the axon is increased leading to a minimal amount of charge or sodium influx threshold value
required for the depolarization of the cell [2, 3]. These effects resulting from the myelin sheath
activity lead to the total speed of conduction of the action potential in the axons [2].
Additionally, there is a marked reduction in the amount of sodium atoms that enter the cell
leading to a reduction in the expenditure of ATP that occurs in the axon during sodium pumping
[2]. The energy efficiency of the axon and in turn the action potential conduction ability is

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increased and the expenditure of energy that occurs in the process of maintenance of the resting
potential of the oligodendrocyte that yields the ensheathing is optimized [2].
In the functioning of the myelinated axons is based fundamentally on the presence of discrete
areas or sites of entry for sodium atoms during the initiation of the action potential [2]. The
nodes of Ranvier are primary sites of sodium entry [2]. At the nodes of Ranvier, there is a break
in the myelin sheath present on the axon and the outer axon makes direct contact with the
extracellular matrix present in bulk [2]. At these points, there are voltage-gated channels where
sodium enters the axon through the glial cells that ensheath the cell [2]. There are several
complex interactions that occur between the axon and the glial cell such as definition of the node
as being free of the sheath, localisation of voltage-gated sodium channels and axonal potassium
cells, attachment of the ends of myelin sheath [2].
Molecular organization and electrical conduction principles in the
healthy node of Ranvier:
In the healthy node of Ranvier, a high concentration of the sodium channels has to ensure by its
molecular level of organization [2]. This results in the occurrence of voltage change of the action
potential to its full extent and thus an increased rapidness in activation of the channels [2]. Most
of the potassium channels are present locally in the juxtaparanodal region of the axon;
additionally, due to a little current that flows beneath the surface of the myelin sheath and these
two events can reduce the capacitance of the axonal region [2]. The nodal length and diameter of
the axon is largely responsible for the conduction of electrical impulses as well [2]. At the
molecular level of organization of the axon, the potassium channels regulate the amount of
current generated by the sodium channels [2, 3].

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The Node of Ranvier in neuropathologies - Multiple sclerosis:
Under normal physiological conditions, the myelinated axons have a safety regulation control
mechanism during transmission by which the electric impulses required for depolarization are
controlled [3]. Due to this, the action potential that gets generated in the node is several folds
higher in magnitude as compared to the required amount of current for the passing on of the
action potential to the subsequent node [3]. In most neuropathologies, there is a marked damage
to the myelin sheath [3]. Multiple sclerosis is characterised primarily by the effect of
demyelination on the axon [3]. When the myelin sheath is damaged, the factor for safety is
compromised [3]. The conditions of the immediate axonal environment greatly affect the success
of electrical conduction in the demyelinated axon [3]. Consequently, several physiological
changes are effected in the axon leading to the loss of the saltatory method of conduction of
electrical impulses [3]. Along with this, there is a marked reduction in the velocity of conduction
and predisposes the block of conduction [3].
Multiple sclerosis is characterized by the inflammation of the CNS along with extensive
demyelination and axonal preservation [4]. It results in lesions in the axon and associated gliosis
[3, 4]. The disease progression can occur in certain primary stages: early stages of inflammation,
full recovery, relapses, neuronal deficit and neurodegeneration, and secondary progression [4]. In
Multiple sclerosis, there is a partial or complete loss of physiological functionality of the axonal
structure [3]. Most associated symptoms such as paresis, ataxia, diplopia, or impairment of
vision are resulted from these changes [3]. The clinical manifestations of the disease depend on
the phase of the disease and differ between patients [3]. Thus, when the fibres subservient of the
specific proportion of conduction or exceed the “safety margin” of electrical conduction, the

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clinical manisfestations of multiple sclerosis occur [4]. Thus, the block of conduction indicates
the failure of the event of propogation of action potential to a specific region on the intact myelin
sheath of the axon [4]. This occurs by depolarization resulting from demyelination,
inflammation, or lesions [3, 4]. Typically, there is a conduction block in the axon due to
inflammation or demyelination due to the exceeding of the safety margin of condution [4].
Conclusion:
Action potentials are conducted in the CNS through normal axons as part of the homeostatic
physiological processes in humans. Such conduction occurs via a saltatory movement and
conduction of electricity. The myelin sheath present on the axon is responsible for the
conduction of impulses. In neuropathologies such as multiple sclerosis, there is demyelination,
inflammation, or lesion formation in the axons leading to a block in conduction. Due to
demyelination, the ion channels and the resultant action potentials undergo depolarization
leading to them exceeding the cell safety margin considerably due to which the conduction of
electric impulses is blocked. This leads to the loss of cognitive functions consequent to the loss
of normal physiological functions of the brain.

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References:
1. Carcamo, L.A. & Attwell, D. 2014. The node of Ranvier in CNS pathology. Acta
Neuropathol, 128(2): 161-175
2. Debanne, D., Campanac, E., Bialowas, A., Carlier, E., & Alcaraz, G. 2011. Axon physiology.
Physiological reviews, 91(2):555-602
3. Compston, A., Ebers, G., Iasmann, H., McDonald, I., Wekerle. H. The Pathophysiology of
multiple sclerosis In Multiple sclerosis third edition Churchill Livingstone Ch 11 pp 359-378
4. Sa, M. J. 2012. Physiopathology of symptoms and signs in multiple sclerosis. Arq
Neuropsiquiatr, 70(9):733-740
5. Alle, H., & Geiger, J.R. 2008. Analog signalling in mammalian cortical axons. Curr Opin
Neurobiol, 18: 314–320.