Neural Synapses Case File

Neural Synapses Case File

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

CASE 5

A woman brings her 68-year-old father to your office for an examination. She states that over the past several years, “he has become increasingly forgetful.” Initially, her father would not remember where he had left his wallet and keys from earlier in the day. Now she has to constantly remind him of what they had just discussed. While he used to be an avid storyteller, he has become much less gregarious of late. Most recently, she states that the neighbors found her father wandering around the block without an explanation of where he was going or from where he had just come. You diagnose her father with Alzheimer disease (AD).

• What is the most likely finding on a postmortem brain biopsy?
• Which neurotransmitter would most likely be deficient?
• What treatments are available for this condition?

ANSWERS TO CASE 5: NEURAL SYNAPSES

Summary: A 68-year-old male with a several-year history of progressive cognitive

decline is diagnosed with Alzheimer disease.

• Biopsy findings: Amyloid plaques and neurofibrillary tangles are clearly visible by microscopy. Amyloid plaques are hard, insoluble plaques of protein fragments that form between neurons. Neurofibrillary tangles consist of insoluble microtubules that accumulate because of abnormal tau proteins.
• Neurotransmitter: The oldest of the three major competing theories on the cause of the disease is the “cholinergic hypothesis” which posits that AD is caused by restricted biosynthesis of acetylcholine, so acetylcholine would be the most deficient.
• Treatments: There is no definitive treatment for AD. Antipsychotic medications or benzodiazepines may be administered to help treat certain behavioral disturbances common with AD.

CLINICAL CORRELATION

Alzheimer disease is the most common degenerative disorder of the brain accounting for 50% of all diagnosed dementias. It results in a relentlessly progressive cognitive decline. Initially, the individual exhibits forgetfulness with day to day occurrences. Items may be frequently misplaced and appointments may go unattended. Following the establishment of memory loss, further cognitive decline becomes more evident. The patient may develop a halting manner to his or her speech because of the failure of recall of certain words. As the speech deficits increase, characteristics of expressive and/or receptive aphasias become more pronounced. Other cognitive difficulties include dyscalculia, disruption of visuospatial orientation, and ideational and ideomotor apraxias. The patient may eventually develop difficulty with locomotion and may become confined to the bedfast state. The incidence and prevalence of AD increase comparably with age. The majority of patients are over the age of 60, but AD has been diagnosed in some patients considerably younger. Certain forms of AD have a familial occurrence, but account for less than 1 percent of all cases. The most well-described familial trends follow an autosomal dominant inheritance. The early onset of AD has also been linked with Down syndrome. The most important aspect of the diagnosis of AD is the exclusion of treatable forms of dementia. While, imaging of the brain may demonstrate diffuse atrophy with thinning of the cerebral gyri and enlargement of the sulci and ventricles in the advanced stages, it is more important to identify mass lesions, such as chronic subdural hematomas, which may account for the symptoms. On histological specimens, AD is associated with the diffuse loss of neurons in the cerebral cortex. In particular, neuronal loss in the nucleus basalis of Meynert is associated with decreased levels of the neurotransmitter acetylcholine. There are intracytoplasmic deposition of neurofibrillary tangles in neurons composed of paired, helical filaments, immunoreactive for tau protein and neuritic plaques composed of paired, helical filaments of fibrillar beta amyloid. In the amyloid hypothesis of AD, it was the deposition of fibrillar beta amyloid in the form of neuritic plaques which was believed to be the main cause of the progressive cognitive dysfunction. However, the spatial and temporal patterns of plaque formation did not correlate well with the level of cognitive decline. Newer research into the pathophysiology of AD points to the role of nonfibrillar amyloid beta peptide (A-β), the precursor of neuritic plaques, accumulating in synapses. This has been termed the synaptic amyloid beta hypothesis. Amyloid precursor protein (APP), a protein, is embedded in the membrane of the presynaptic terminal of the neuron. Cleavage of APP results in the release of A-β into the synapse which acts as a synaptotoxin impairing glutaminergic transmission and compromising synaptic function. The elucidation of this new model of AD may point to the development of new therapeutic treatments in the future.

APPROACH TO NEURAL SYNAPSES

Objectives

1. Identify the parts of the neural synapse.
2. Describe the two types of neural synapses.
3. Know how synapses function.

Definitions

Synaptic bouton: The terminal end of an axon.

Synaptic cleft: The space between the synaptic bouton and the postsynaptic cell.

Electrical synapses: A type of synapse connected by gap junctions that allows for the direct propagation of an electrical signal.

Chemical synapses: A type of synapse utilizing neurotransmitters from the synaptic bouton which diffuse across the synaptic cleft and bind to receptors on the postsynaptic cell.

DISCUSSION

Synapses are the means by which neurons communicate with one another. On an average, a single neuron will receive approximately 1000 different synapses to process. In its simplest form, a synapse consists of the synaptic bouton or terminal, the terminal end of the axon; the synaptic cleft, the space between the presynaptic and postsynaptic cell; and the postsynaptic terminal. The postsynaptic terminal can be the dendrite or soma of another neuron or even a muscle fiber. The synaptic cleft is not simply an open space, but instead is spanned by membrane proteins from both terminals which form connections to maintain the distance between the two cells (Figure 5-1).

There are two types of synapses in the nervous system, electrical and chemical synapses. An electrical synapse is only 3–4 nm wide and the signal can travel bidirectionally, whereas the chemical synaptic cleft is much larger, measuring approximately 20-40 nm, with the signal traveling more slowly and in one direction, either to another neuron or muscle cell. The majority of synapses in the brain are chemical.

In an electrical synapse, the pre- and postsynaptic cells are connected via gap junctions that allow for communication of the cytoplasm of both cells, accounting for the short distance between the two cells. This provides a lowresistance pathway for the direct flow of electrical potential from one cell to the other. Action potentials that reach the presynaptic terminal directly depolarize the postsynaptic membrane. If the depolarization reaches the threshold for the postsynaptic membrane, an action potential can be generated and propagated through that cell.

Figure 5-1. Schematic drawing of a synaptic terminal.

The transmission of the electrical signal occurs through specialized proteins which physically connect the two cells. Gap junctions consist of two sets of hemichannels or connexons, one each on the pre- and postsynaptic cell membranes. Connexons are in turn composed of six identical, membranespanning protein subunits called connexins. The connexins arrange in a radial array with a central open channel. Proteins on the extracellular side of the connexins identify and link with proteins on the postsynaptic connexins to form the complete conducting channel. Like voltage-gated ion channels, gap junctions can undergo conformational changes to either open or close the channel depending upon the local milieu. These gap junctions allow for the nearly instantaneous transmission of electrical signal. Because of the nature of the synapse, the pre- and postsynaptic membranes lie in very close apposition to one another.

Chemical synapses must convert an electrical signal, the action potential, into a chemical signal, neurotransmitter release, which diffuse across the synaptic cleft to affect the postsynaptic cell. The presynaptic terminal contains large numbers of membrane-bound vesicles. These synaptic vesicles are lined by specialized membrane proteins and are formed from the invagination of the membrane of the synaptic terminal. The vesicles contain proteins and amino acids manufactured from the endoplasmic reticulum and Golgi bodies in the soma and transported down the axon to the terminal via fast anterograde axonal transport by the action of kinesin association to microtubules. These neurotransmitters comprise the chemical messenger system of the nervous system and are concentrated in vesicles clustered around a region of the presynaptic terminal called the active zone. These vesicles remain in reserve until needed for secretion.

When an action potential reaches the terminal, it simply escapes through the ion channels in the presynaptic cell. However, it causes a series of reactions resulting in synaptic vesicles binding to the membrane of the presynaptic cell. Depolarization opens Ca2+ channels, allowing Ca2+ to enter the axon terminal and phosphorylate the vesicle-binding protein synapsin which frees the vesicle from the actin microfilaments, and binds to the active zone. Vesicle and plasma membrane proteins undergo Ca2+-dependent association and the vesicle fuses to the plasma membrane and releases the NT by exocytosis into the synaptic cleft. The vesicle membrane is recaptured from the synaptic terminal plasma membrane to prevent enlargement of the nerve ending and provide a constant supply of vesicles. The neurotransmitters then diffuse across the synaptic cleft and bind to receptors on the postsynaptic membrane.

Based upon the type of neurotransmitter and receptor, the chemical synapse can result in either an excitatory or inhibitory postsynaptic potential. Excitatory neurotransmitters result in a depolarization of the postsynaptic cell. Inhibitory neurotransmitters hyperpolarize the postsynaptic cell. Proteins such as dynein (which associates vesicle with microtubule) used for synaptic transmission are targeted and returned to cell body to be recycled through a process called slow retrograde axonal transport.

Based on their structural and functional characteristics in the nervous system, neurotransmitter receptors can be classified into two broad categories: metabotropic and inotropic receptors. Inotropic receptors form transmembrane ion channels that open and allow transcellular flow of ions upon the binding of a chemical messenger (ligand), as opposed to an electrical potential changes as with voltage-gated ion channels or mechanical changes as with stretch-activated ion channels. Metabotropic receptors, on the other hand, are indirectly linked with ion channels rather than forming them. Upon binding of a ligand, the metabotropic receptor leads to a cascade of intracellular signals which then results in opening of the transmembrane ion channel. Because the transmission of the signal from the presynaptic cell to the postsynaptic cell relies on the diffusion of neurotransmitters, it is significantly slower than an electrical synapse. However, unlike an electrical synapse, the chemical synapse is capable of amplification of the initial signal. Many vesicles, each containing thousands of neurotransmitters, release their contents into the synaptic cleft. This process can lead to the activation of thousands of postsynaptic receptors following binding of the neurotransmitter. Transmission is terminated in the synapse by diffusion of the transmitter from the active zone by chemical degradation by enzymes in the synaptic cleft (ie, acetylcholinesterase), and reuptake of the neurotransmitter into pre- and postsynaptic neurons.

The development of the neural synapse relies partially on several specialized synaptic laminin glycoproteins. Laminin 11, concentrated in the synaptic cleft, acts as an inhibitor to Schwann cells in the neuromuscular junction to prevent them from entering into the cleft. This allows the pre- and postsynaptic cells to directly oppose one another and helps maintain the long-term stability of synapses and allows for the rapid transmission of information across the synaptic cleft. Laminin-β-2 binds directly to calcium channels, which are critical for the release of neurotransmitters in the presynaptic membrane at the neuromuscular synapse. This leads to clustering of calcium channels and the recruitment of other presynaptic components to form the active zone of the presynaptic membrane. Perturbations of either of these synaptic laminin glycoproteins may lead to the pathogenesis of synaptic disease.

COMPREHENSION QUESTIONS

[5.1] A patient presents to your office complaining of weakness and diplopia. After a thorough workup, she is diagnosed with myasthenia gravis, a disease caused by autoimmune destruction of acetylcholine neurotransmitter receptors. In what part of the synapse are these receptors located?

A. Presynaptic membrane

B. Postsynaptic membrane

C. Synaptic cleft

D. Synaptic vesicle

[5.2] On electron microscopic examination of the neuromuscular junction of the patient from the previous question, you note that on one side of the synaptic cleft there are numerous round structures clustered together. A sample of one of these structures shows it to contain acetylcholine. What is the name of the area in question?

A. Presynaptic terminal

B. Active zone

C. Postsynaptic membrane

D. Terminal bouton

[5.3] When stimulated by an action potential, the vesicles seen under EM in the previous question will fuse with the presynaptic membrane. Where will the contents of the vesicles be released?

A. Presynaptic cytoplasm

B. Postsynaptic cytoplasm

C. Synaptic cleft

D. Golgi complex

Answers

[5.1] B. Acetylcholine receptors are located on the postsynaptic membrane. There are a variety of different types of acetylcholine receptors, but those affected in myasthenia gravis are inotropic and located on the postsynaptic membrane in the neuromuscular junction. In patients with myasthenia gravis, acetylcholine is released appropriately into the synaptic cleft when stimulated, but the target for the neurotransmitter is reduced, so muscle cells are insufficiently stimulated, resulting in weakness.

[5.2] B. The portion of the presynaptic neuron containing synaptic vesicles is called the active zone. The round structures in the question are synaptic vesicles, as evidenced by the fact that they contain acetylcholine, a neurotransmitter. Presynaptic terminal and terminal bouton are synonyms, and refer generally to the end of the axon from which neurotransmission occurs, but neither is as specific for the location of the synaptic vesicles as the active zone. The postsynaptic membrane contains neurotransmitter receptors, but not synaptic vesicles.

[5.3] C. On stimulation, synaptic vesicles fuse with the presynaptic membrane and release their contents (neurotransmitters) into the synaptic cleft, where they diffuse across and interact with receptors on the postsynaptic membrane. Neurotransmitters do not actually enter the postsynaptic cells; they interact with membrane proteins and cause their effects through the receptors. Likewise, neurotransmitters are typically not found in large quantities in the presynaptic neuron cytoplasm, they are contained in the synaptic vesicles. Synaptic vesicles do not fuse with or release their contents into the Golgi complex; although, depending on the type of neurotransmitter, it may originate there.

NEUROSCIENCE PEARLS ❖ There are two types of synapses in the nervous system: electrical synapses and chemical synapses. ❖ Electrical synapses contain gap junctions which physically connect adjacent neurons and allow for faster conduction of the signal. ❖ Chemical synapses comprise the majority of synapses and convert the electrical signal (the action potential) into a chemical signal (the release of a neurotransmitter). ❖ Presynaptic terminals contain larger numbers of preformed membranebound vesicles full of neurotransmitters, which are released via calcium-dependent exocytosis once the action potential reaches the terminal. ❖ Inotropic receptors directly form an ion channel pore that allows movement of ions once the receptor is activated. ❖ Activation of metabotropic receptors (ie, via binding of a ligand) leads to a cascade of intracellular signals that then results in opening of an adjacent ion channel.

REFERENCES

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

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

Zigmond MJ, Squire LR, Bloom FE, Landis SC, Roberts JL, eds. Fundamental Neuroscience. 2nd ed. San Diego, CA: Academic Press; 1999.

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