The Neuron Case File

The Neuron Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 2

An otherwise healthy 54-year-old female comes to the physician’s office complaining of weakness initially involving her hands and progressing to her legs over several months. She states that her hands feel stiff and clumsy and that she has difficulty buttoning her clothes or using her keys. She has fallen several times in the past couple of weeks walking up and down her stairs at home. Lately, both she and her husband have noticed that she will “stumble over words” when she talks. She denies any funny sensations or numbness and has no family history of neurological disease.

On physical examination she is alert, appropriate, and oriented to person, place, and time. Her cranial nerves are intact except for some subtle fasciculations (involuntary muscle twitches) of her tongue. There is some mild weakness in strength testing of her right arm and leg with pronator drift. Muscle stretch reflexes are brisk in upper extremities, but reduced in her right leg. She also has difficulty with rapid alternating movements of her right arm. There are no abnormal findings on sensory examination. The physician has a presumptive diagnosis of amyotrophic lateral sclerosis (ALS) and explains that this is an upper motor neuron disease.

• What part of the nervous system is likely to be involved?
• Explain the mechanism of the fasciculations with this disease?
• What are the pathological findings with this disease?

ANSWERS TO CASE 2: THE NEURON

Summary: A 54-year-old female with progressive weakness of her arms and legs with subtle speech difficulties is diagnosed with ALS.

• Part of nervous system affected: The central nervous system (CNS), specifically motor neurons.
• Fasciculations: ALS is a progressive, neurodegenerative disease affecting motor neurons, cells within the CNS that caused voluntary muscle movement. The loss of signal communication to the muscles because of the degeneration of these cells leads to muscle atrophy which manifests itself in fasciculations.
• Pathology: Loss of motor neurons in the anterior horns of the spinal cord and brainstem nuclei along with degeneration of the corticospinal tracts in the spinal cord.

CLINICAL CORRELATION

ALS is a progressive degenerative disorder of the motor neurons of the spinal cord and brainstem nuclei and corticospinal tracts. In its classical presentation, patients in their sixth decade initially complain of difficulty with fine finger movements and stiffness and weakness of the fingers and hands. The patients can also experience cramps or fasciculations of the muscles in the upper extremities. As time progresses, atrophic weakness involves both upper extremities and spasticity and hyperreflexia develops in the lower extremities. Even the muscles of the neck, tongue, pharynx, and larynx become involved. Depending on the extent of involvement of the various motor neurons, a mixed upper and lower motor neuron disease becomes evident. There are no cognitive, sensory, or autonomic disturbances in this disease. An electromyelogram (EMG) obtained for confirmatory purposes reveal widespread fibrillations and fasciculations, evidence of active denervation and reinnervation of the muscles. Analysis of CSF may reveal normal or slightly elevated protein levels. Unfortunately, the etiology of ALS is unknown. As the disease reaches its ultimate conclusion, the patient is left in a flaccid paralysis of all voluntary muscles with the exception of extraocular and sphincter muscles. Treatment is directed toward minimizing the disability. For instance, medications such as baclofen and diazepam can be used to treat spasticity. The median survival from onset of symptoms is three to four years, although individuals can live a normal life span if proper care is available.

APPROACH TO THE NEURON

Objectives

1. Describe the role and structure of a neuron.
2. Know the classification of neurons based upon morphology.
3. Know the classification of neurons based upon function.

Definitions

Cytoskeleton: The internal network of fibers that form the framework inside a cell. In the neuron, the cytoskeleton consists of three types of

filaments: microtubules, neurofilaments, and microfilaments and determines the shape of the neuron, provides cell rigidity, and creates a mechanism for intracellular transport.

Soma: The cell body of the neuron, which contains all the organelles and acts as the metabolic center of the cell.

Dendrites: Armlike extensions protruding from the cell membrane that increase the surface area of the neuron and receive signals from other neurons.

Axon: The main conducting unit for carrying electrical signals, action potentials, to other cells. Action potentials are formed at the axon hillock, the origin of the axon from the cell body, and are propagated down the axon in a rapid, all-or-none transmission to the next cell.

Presynaptic terminal: This is the end of axon that forms a synapse or neurochemical cleft with the next cell (neural, muscular, etc). Signals are transmitted across the synapse via the release of neurotransmitter into the synaptic cleft that diffuse into the postsynaptic cell, chemically triggering a physiological response.

DISCUSSION

Morphological Features

Neurons, the basic functional components of the brain, are cells that act as the main signaling units of the nervous system. The cytoskeleton of the neuron is composed of three types of filaments, each constructed from different classes of proteins. Together they form the cytoskeletal structure of the neurons that determine the shape of the neuron, provide stiffness to the cell, and create a mechanism for intracellular transport.

• Microtubules, the largest of the filaments, are constructed from 13 different types of protofilaments in a circular array and serve to maintain the neuron’s processes. The protofilaments are formed by two subunits, alpha and beta tubulin, in an alternating pattern. Microtubules are also involved in axoplasmic transport, or movement of various cell components along an axon such as mitochondria, lipids, synaptic vesicles, proteins, and so on.
• Neurofilaments or intermediate filaments are approximately 10 nm in diameter and are more abundant than either microtubules or microfilaments. Neurofilaments are made from strands of proteins that pair into a helical structure. The pairs of proteins then twist together to form larger protofilaments. Four protofilaments combine to form the final neurofilament. Neurofilaments can form cross-links with microtubules to provide stiffness and shape to the cell. Within the context of Alzheimer disease, neurofilaments are modified to form pathological protein aggregates called neurofibrillary tangles.
• Microfilaments are, as the name implies, the thinnest of the fiber types at approximately 3-5 nm and are formed by the polymerization of the protein actin to form a double helical structure. Microfilaments are located at the periphery of the cell adjacent to the cytoplasm of the cell. Together with multiple types of actin-binding proteins, they assist in the dynamic functions of the cell.

There are four distinct morphological features in a typical neuron.

• The cell body or soma acts as the metabolic center of the neuron and contains the ultrastructural organelles, such as the nucleus (DNA storage and ribosome production), endoplasmic reticulum (protein synthesis), mitochondria (energy through ATP production), lysosomes (waste disposal), and vesicles (packaging and transport) necessary to carry out basic metabolic functions.
• Multiple short dendrites branch out from the cell body in a treelike fashion. The dendrites function mainly to increase the surface area of the neurons and receive signals from other neurons.
• A single axon arises from the cell body and serves as the main conducting unit for carrying electrical signals to other neurons and muscles. The electrical signals, called action potentials, are rapid, all-or-none transmissions down the length of the axon. Action potentials are formed at the origin of the axon from the cell body called the axon hillock. To facilitate transmission of the electrical signal, axons can be wrapped in myelin sheaths produced by oligodendrocytes and Schwann cells.
• The presynaptic terminal at the end of the axon forms synapses with the postsynaptic cell, that is, other neurons or muscles. When the action potential reaches the presynaptic terminal, a cascade of events occurs culminating in the release of neurotransmitters into the synaptic cleft. The neurotransmitters diffuse to the postsynaptic cell, which in turn triggers certain physiological responses.
  

Ramon y Cajal, using silver staining techniques developed by Camillo Golgi, first noticed that the shape of the neuron could be used for classification. Based upon the number of axons and dendrites which originate from the cell body, neurons can be classified into several broad groups.

• Unipolar neurons are the simplest nerve cells and have a single process emerging from the cell body. This process branches with one branch functioning as the axon and the other branches functioning as the dendrites. They are found throughout the central nervous system of invertebrates and in the autonomic nervous system of vertebrates.
• Bipolar neurons have two processes attached to an oval-shaped cell body. One process functions as the dendrite and carries information from the periphery of the organism. The other process functions as the axon carrying information toward the central nervous system. Bipolar neurons are found in the retina of the eye and the olfactory epithelium of the nose.
• Pseudo-unipolar neurons are a variant of the bipolar neuron and have a single process which emerges from the cell body. This single process splits into two; one functions as the dendrite carrying information from the periphery to the cell body and the other functions as the axon transmitting the information to the central nervous system. They are found in the dorsal root ganglia of the spinal cord and relay touch, pressure, and pain sensations from the extremities to the spinal cord.
• Multipolar neurons are the main neuron type in the mammalian central nervous system. These neurons have a single axon and multiple dendrites emerging from the cell body. Multipolar neurons vary in number, size, and length of processes depending on the number of synaptic contacts they make with other neurons.

Functional Classification

Neurons can also be classified according to the function that they serve within the nervous system.

• Sensory or afferent neurons carry information from the body to the central nervous system. Sensory information can include pain, pressure, touch, and joint position sense, among others.
• Motor neurons carry commands from the brain and spinal cord to muscles and glands in the periphery.
• Interneurons are all other neurons which do not fit into the previous two groups. Interneurons carry information within the nervous system and synapse on neighboring or distant neurons.

All behaviors are mediated by a series of neurons that form signaling networks. For instance, mechanoreceptors carry information concerning joint position through sensory neurons to the spinal cord. This information is transmitted through various interneurons in the spinal cord and brain to allow the central nervous system to process and determine where an individual’s limb is in relation to the body and space. Once a decision is made to move the extremity, a variety of interneurons transmits the information to motor neurons to relay the final command to the muscles. In this role, interneurons, through a variety of neurotransmitters, can act to either excite or inhibit other neurons.

Spinal Cord Neurons

Neurons within the spinal cord are organized into a somatosensory and motor neurons. Somatosensory neurons form an ascending tract of neurons that run up the spinal cord transmitting information about touch, proprioception (balance and selfawareness), vibration, pain, and temperature. Motor neurons form a descending tract of neurons that run down the spinal cord to control muscle function throughout the body. The cord itself is divided into several sections axially: the dorsal, lateral, and ventral horns. Somatosensory neurons from the body run into the dorsal horn where they synapse onto interneurons in the lateral horn that transmit information via the ascending tracts to the brain, or in the case of a spinal reflex, directly to motor neurons in the ventral horn. Motor neurons running out of the ventral horn are similarly controlled by direct reflex signaling from a sensory neuron, or by efferent (motor) neurons traveling down the descending tract from the brain.

COMPREHENSION QUESTIONS

[2.1] A 35-year-old man is brought to the emergency room (ER) by the paramedics after having his left hand crushed in an industrial accident. He is in excruciating pain. What morphologic type of neuron is responsible for transmitting the pain signal from his mangled stump to his CNS?

A. Bipolar

B. Multipolar

C. Pseudo-unipolar

D. Unipolar

[2.2] When an action potential reaches the presynaptic terminal, a set of complex cellular functions is set in motion, involving a wide variety of different proteins with different functions. How do the majority of the elements involved in this signaling cascade come to be found in the presynaptic terminal?

A. Diffusion

B. They are synthesized in the presynaptic terminal

C. They are transported there by kinesin interaction with microtubules

D. They are transported there by dynein interaction with microtubules

[2.3] After a neurotransmitter is released from the presynaptic terminal, it interacts with a postsynaptic neuron to cause its effect. Which morphologic feature of the neuron is responsible for receiving synaptic transmissions and transmitting these postsynaptic signals to the rest of the cell?

A. Axon

B. Dendrite

C. Soma

D. Terminal bouton

Answers

[2.1] C. These neurons of the dorsal root ganglia are pseudo-unipolar. Pain is transmitted from sensory end organs to sensory neurons with cell bodies located in the dorsal root ganglia, which then transmit the signal to second-order sensory neurons in the spinal cord. In function they are quite similar to bipolar neurons, in that they have one large dendrite and one large axon, but these processes fuse prior to entering the cell body, so there is in fact only one process leaving the soma.

[2.2] C. The interaction between the cytoskeletal microtubules and carrier molecules is responsible for fast axonal transport. Kinesin is responsible for anterograde (away from the cell body) transport and dynein is responsible for retrograde (toward the cell body) transport. Recall that almost all macromolecules and organelles found in the presynaptic terminal were originally synthesized in the cell body, but that the axon is far too long to rely upon diffusion for the molecules to reach the axon.

[2.3] B. Dendrites are responsible for transmitting signals toward the cell body. Axons are the second set of neural processes which transmit signals away from the cell body. The soma is responsible for housing virtually all of the biomolecular machinery of the cell, and the terminal bouton houses the presynaptic neurotransmitter-releasing system.

NEUROSCIENCE PEARLS ❖ The cytoskeleton of the neuron is composed of three types of filaments: microtubules, neurofilaments, and microfilaments. ❖ Microtubules are involved in the movement of various cell components along an axon. ❖ There are four distinct morphological features in a typical neuron including the soma, dendrites, axon, and presynaptic terminal. ❖ Neurons can be classified into unipolar cells, bipolar cells, pseudounipolar neuron, and multipolar neurons according to the number of axons and dendrites which originate from the cell body. ❖ Neurons can be classified as sensory/afferent neurons, motor/efferent neurons, or interneurons according to function. ❖ Interneurons synapse onto neighboring or distant neurons and can act either to excite or inhibit other neurons.

REFERENCES

Bear MF, Connors B, Paradiso M, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 5th ed. New York: McGraw-Hill; 2000. 

Purves D, Augustine GJ, Fitzpatrick D, et al., eds. Neuroscience. 3rd ed. Sunderland, MA: Sinauer Associates, Inc.; 2004.

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