ANATOMY AND PHYSIOLOGY

The Neuromuscular Junction: Function, Structure & Physiology Synaptic Transmission In order for skeletal muscle to contract, it must first be stimulated by a motor neuron. The space between the motor neuron and the skeletal muscle cell is simply referred to as a synapse. More specifically, the synapse between a motor neuron and a skeletal muscle cell is referred to as a myoneural or neuromuscular junction. If you break down these terms, the names will make better sense. 'Myo'- means muscle, and 'neuro'- refers to nerves. Regardless of the name, the synapse is a real space across which the excitatory impulse must travel before the muscle contracts.

A neuromuscular junction between a motor neuron and skeletal muscle cell Synaptic transmission includes all the events within the synapse leading to excitation of the muscle. Let me make a quick note that other synapses occurs between other cells for example, nerve to nerve and nerve to gland. For example, the adult human brain is thought to contain 100-500 trillion synaptic connections, and those are in between neurons. In this lesson, we will describe the anatomy of a neuromuscular junction and then discuss the events of synaptic transmission. Anatomy Of A Synapse The image you see on the screen illustrates a synapse between a neuron and a muscle cell. The neuron is sending the transmission and is thus referred to as the pre-synaptic cell, while the muscle is receiving the transmission and is referred to as the post-synaptic cell. Neurotransmitters are molecules stored in the pre-synaptic cell that are secreted into the synapse. Neurotransmitters, in turn, bind to receptors on the post-synaptic cell membrane, and these receptors are specific for that neurotransmitter. Think of the neurotransmitter-receptor relationship as a lock and a key, where only one key will fit that lock. The synaptic cleft refers to the space between the two cells and is only about 20 nanometers wide. Physiology Of A Synapse Now that we know what makes up a synapse, we're ready to describe the function of the neuromuscular junction. It's important to keep the big picture in mind. So what is that big picture? Synaptic transmission carries the excitatory signal from the neuron to the muscle cell, much like a bridge could connect two land masses.

A diagram of a synapse between a muscle cell and neuron

Let's start with the motor neuron. Calcium enters the excited neuron, and the calcium stimulatesexocytosis of the neurotransmitter. Where does the neurotransmitter go but into the synaptic cleft. The neurotransmitter secreted by the somatic motor neurons is acetylcholine. So the acetylcholine diffuses across the cleft and binds to acetylcholine receptors within the muscle cell membrane. Like a key unlocking a door, acetylcholine opens ion channels, and sodium ions diffuse into the muscle cell. It's important to note that acetylcholine does not remain in the synaptic cleft forever, but rather an enzyme called acetylcholinesterase catalyzes the breakdown of acetylcholine, and where is it located - in the synaptic cleft. This enzyme breaks down acetylcholine and therefore prevents overcontraction, or prevents contraction for lasting longer than necessary. Since sodium is a positive ion, it depolarizes and thus excites the skeletal muscle cell membrane as it enters. Now the excitatory impulse has transferred from the motor neuron to the muscle cell, much like a car would cross a bridge from one land mass to the next.

Calcium is released into the cell interior, causing contraction.

Invaginations of the cell membrane referred to asT-tubules will then carry that excitatory impulse deep into the muscle cell's interior. The excitatory impulse then triggers release of calcium into the cell's interior coming from the sarcoplasmic reticulum or simply the SR. Recall that calcium triggered secretion of acetylcholine in the motor neuron. What's going on here? In the muscle, calcium will trigger contraction of the muscle cell. Neuromuscular Disease Neuromuscular disorders can result from problems occurring at the neuromuscular junction. For example, myasthenia gravis is an autoimmune disorder in which muscle weakness is caused byantibodies that target the acetylcholine receptor on the skeletal muscles. Those antibodies will target the receptor, and then the receptor is destroyed by own our immune system (that's why it's called an autoimmune disorder). Without sufficient receptors for acetylcholine, neurotransmission is slowed and contraction is inhibited. Now there is no current cure for this disease; however, acetylcholinesterase inhibitors, such as neostigmine, can improve muscular function by at least slowing the degradation of acetylcholine in the synapse. How muscles work continued? As explained on the previous page (The Sliding-Filament Theory of Muscle Action), muscles contract and relax as a result of two different types of filaments (called thick filaments, and thin filaments) moving backwards and forwards across each other.

The next question is: What causes such movements to occur? Muscles (and other tissues) are controlled by the nervous system - which consists of nerve cells called neurones. Of the three types of neurones (motor neurones, sensory neurones and relay neurones), motor neuronesinstruct skeletal muscle cells to perform the series of actions that lead to sliding filaments and hence muscle contraction. A single motor neurone together with all of the muscle fibers (muscle cells) to which it is attached, and therefore stimulates, is called amotor unit.

Stimulation of the one neurone of a motor unit results in simultaneous contraction of all of the muscle cells in that motor unit. The number of muscle cells in a motor unit, i.e. the ratio of motor neurones (nerve cells) to muscle cells, varies according to the type and function of the muscle of which it is a part. For example, delicate muscles of facial expression are not developed for high load-bearing actions but rather to convey a huge variety of subtle movements of skin. These muscles therefore consist of motor units containing only a few (sometimes less than 10) muscle cells each. However, larger more powerful muscles - such as the biceps brachii and the gastrocnemius - contain motor units of up-to 2000 muscle cells each.

Neuromuscular junctions (NMJs) are the locations and means by which the motor neurones of the nervous system instruct the muscle cells of the muscular system to take actions - actions that, in turn, lead to the movement of muscles and the attached structures such tissues, bones, limbs etc.. Anatomical Description of a NMJ: Each neuromuscular junction consists of the axon terminal of a motor neuron and the motor end plate of a muscle fibre.

The Motor Neurone Part: The long processes of neurones are called "axons". As the axon of a motor neurone enters the structure of skeletal muscle it forms many branches called "axon terminals". There is a bulbous swelling called a "synaptic end bulb" at the extreme/end of each axon terminal. Each synaptic end bulb contains many synaptic vesicles, each of which contains an important chemical neurotransmitter called "acetylcholine", which is often abbreviated to simply "ACh". The Muscle Fiber Part: The part of the sarcolemma of the muscle cell that is in closest proximity to the synaptic end bulb is called the "motor end plate".

Normal Anatomy and Physiology of the Neuromuscular Junction The skeletal muscle fibers are innervated by large myelinated nerve fibers that originate from large motoneurons in the anterior horns of the spinal cord. Each nerve fiber normally branches and stimulates from three to several hundred skeletal muscle fibers. Each nerve ending makes a junction, called the neuromuscular junction, with the muscle fiber near its midpoint. As shown in the figure below, the nerve fiber forms a complex of branching nerve terminals that invaginate into the surface of the muscle fiber but lie outside the muscle fiber plasma membrane. The entire structure is called the motor end plate.

This is where the junction between a single axon terminal and the muscle fiber membrane exists. The invaginated membrane is called the synaptic gutter, and the space between the terminal and the fiber membrane is called the synaptic cleft. At the bottom of the gutter are numerous smaller folds on the muscle membrane called subneural clefts, which increase the surface area at which the synaptic transmitter can act. In the axon terminal are many mitochondria that supply adenosine triphosphate (ATP), the energy source that is used for synthesis of an excitatory transmitter acetylcholine. The acetylcholine in turn excites the muscle fiber membrane. Acetylcholine is synthesized in the cytoplasm of the terminal, but it is absorbed rapidly into many small synaptic vesicles, about 300,000 of which are normally in the terminals of a single end plate. In the synaptic space are large quantities of the enzyme acetylcholinesterase, which destroys acetylcholine a few milliseconds after it has been released from the synaptic vesicles. Acetylcholine Aids in Muscle Contraction Normally, a nerve impulse reaches the neuromuscular junction which allows the release of acetylcholine from the axon terminals into the synaptic cleft. In detail, acetylcholine is released from the synaptic vesicles at the neural membrane of the neuromuscular junction which contains voltage-gated calcium channels. These channels open and allow calcium ions to diffuse from the synaptic cleft to the interior of the nerve terminal. The calcium ions attract the acetylcholine vesicles, drawing them to the neural membrane adjacent to the dense bars. The vesicles then fuse with the neural membrane and empty their acetylcholine into the synaptic cleft by the process of exocytosis. On the other hand, the muscle fiber membrane contains acetylcholine receptors which are acetylcholine-gated ion channels. Its principal effect is to allow large numbers of sodium ions to pour to the inside of the fiber, creating a local positive potential change inside the muscle fiber membrane, called the end plate potential. In turn, this end plate potential initiates an action potential that spreads along the muscle membrane and thus causes muscle contraction. Once the acetylcholine is released into the synaptic cleft, it continues to activate the acetylcholine receptors. However, acetylcholine will be removed rapidly by the enzyme acetylcholinesterase and the diffusion of the small amount of acetylcholine out of the synaptic cleft, preventing it to act on the muscle fiber membrane. Fatigue of the neuromuscular junction or the repetitive stimulation of the nerve fiber at rates greater than 100 times per second for several minutes often diminishes the number of acetylcholine vesicles that it may fail to pass into the muscle fiber.