Synapse and NMJ

Dr Irum Rehman

DEFINITION

“ The site of connection of motor neuron with skeletal muscle making a functional contact is called as NEUROMUSCULAR JUNCTION.”

Neuromuscular Junction

- Neuromuscular Junction

A neuromuscular junction exists between a motor neuron and a skeletal muscle.

- Synapse

A junction between two excitable tissues.

INNERVATION OF SKELETAL MUSCLE FIBERS

Large, myelinated nerve fibers Originate from large motor neurons in the

anterior horns of the spinal cord Each nerve fiber, branches and stimulates

from three to several hundred skeletal muscle fibers

The action potential initiated in the muscle fiber by the nerve signal travels in both directions toward the muscle fiber ends

MOTOR END PLATE

• 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

• Entire structure - motor endplate.

• Covered by one or more Schwann cells that insulate it from the surrounding fluids.

AXON TERMINAL

• SYNAPTIC VESICLES – Size 40 nanometers – Formed by the Golgi apparatus in the cell body

of the motor neuron in the spinal cord. – Transported by axoplasm to the

neuromuscular junction at the tips of the peripheral nerve fibers.

– About 300,000 of these small vesicles collect in the nerve terminals of a single skeletal muscle end plate.

• MITOCHONDRIA – Numerous– Supply ATP – Energy source for synthesis of excitatory

neurotransmitter, acetylcholine

• DENSE BARS – Present on the inside surface of neural

membrane

• VOL TAGE GATED CALCIUM CHANNELS

– Protein particles that penetrate the neural membrane on each side 0f dense bar

– When an action potential spreads over the terminal, these channels open and calcium ions diffuse to the interior of the nerve terminal.

– The calcium ions, exert an attractive influence on 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 space by the process of exocytosis

– Calcium acts as an effective stimulus for causing acetylcholine release from the vesicles

– Acetylcholine is then emptied through the neural membrane adjacent to the dense bars and binds with acetylcholine receptors in the muscle fiber membrane

MUSCLE FIBER MEMBRANE

• SYNAPTIC TROUGH – The muscle fiber membrane where it is

invaginated by a nerve terminal and a depression is formed

• SYNAPTIC CLEFT – The space between the nerve terminal and

the fiber membrane is called the synaptic space or synaptic cleft

• SUBNEURAL CLEFT – Numerous smaller folds of the muscle

membrane at the bottom of the gutter– Greatly increase the surface area.

• ACETYLCHOLINE RECEPTORS – Acetylcholine-gated ion channels– Located almost entirely near the mouths of

the sub neural clefts lying immediately below the dense bar areas

ACETYLCHOLINE RECEPTORS

• Acetylcholine-gated ion channels

• Molecular weight -275,000

• SUBUNITS – Two alpha, one each of beta, delta, and

gamma – Penetrate all the way through the membrane– Lie side by side in a circle- form a tubular

channel – Two acetylcholine molecules attach to the two

alpha subunits, opens the channel

• RESTING STATE – 2 Ach molecules not attached to the alpha

subunit – Channel remains constricted

• OPENED Ach CHANNEL

– 2 Ach molecules attached to the alpha subunit of receptor

– Diameter- 0.65 nanometer– Allows important positive ions—SODIUM,

potassium, and calcium to move easily through the opening.

– Disallows negative ions, such as chloride to pass through because of strong negative charges in the mouth of the channel that repel these negative ions.

• SODIUM IONS

– Far more sodium ions flow through the acetylcholine channels to the inside than any other ions

– The very negative potential on the inside of the muscle membrane, –80 to –90 mili volts, pulls the positively charged sodium ions to the inside of the fiber

– Simultaneously prevents efflux of the positively charged potassium ions when they attempt to pass outward

• END PLATE POTENTIAL

– Opening the acetylcholine-gated channels allows large numbers of sodium ions to pour to the inside of the fiber

– Sodium ions carry with them large numbers of positive charges

– Creates a local positive potential change inside the muscle fiber membrane, called the end plate potential.

– End plate potential initiates an action potential that spreads along the muscle membrane

– Causes muscle contraction

Events of Neuromuscular Junction

1. Propagation of an action potential to a terminal button of motor neuron.

2. Opening of voltage-gated Ca2+ channels.3. Entry of Calcium into the terminal button.4. Release of acetylcholine (by exocytosis).5. Diffusion of Ach across the space.6. Binding of Ach to a receptor on motor

end plate.

Examples of Chemical Agents and Diseases that Affect the Neuromuscular

JunctionMechanism that Chemicals or DiseaseAlters Release of Acetylcholine

* Cases explosive release of acetylcholine * Black widow spider venom* Blocks release of acetylcholine * Clostridium botulinum toxin

Block acetylcholine Receptor

* Bind reversibly * Curare* Auto antibodies inactivate acetylcholine * Myasthenia gravis receptors

Prevents inactivation of acetylcholine

* Irreversibly inhibits acetylcholinesterase * Organophosphates * Temporary inhibits acetylcholinesterase * Neostigmine

Synapse

• Definition

• Types

• Anatomical and Physiological

Properties/ Characteristics

• A combination of neurotransmitter and a synapse will always be either

1Excitatory Or

2 Inhibitory

One-way conduction

• Synapses generally permit conduction of

impulses in one-way i.e.

– from pre-synaptic to

– post-synaptic neuron.

Spatial Summation in Neurons• Excitation of a single presynaptic terminal??

– 0.5 to 1 millivolt• 10 to 20 millivolts - required to reach threshold• Many presynaptic terminals are

usually stimulated at the same time.• Add to one another until neuronal excitation• Spatial summation

– Summing simultaneous postsynaptic potentials by activating multiple terminals on widely spaced areas of the neuronal membrane

Temporal Summation

• A presynaptic terminal fire– changed postsynaptic potential – lasts up to 15 milliseconds

• Second opening of the same channels -increase the postsynaptic potential to - still greater level

• Successive discharges from a single presynaptic terminal

• Rapid enough- add to one another• This type of summation is called Temporal

summation.

Facilitation of Neurons

• If the summated postsynaptic potential is

excitatory………….

• But has not risen high enough to reach the

threshold

• The neuron is said to be facilitated.

• Another excitatory signal - excite the neuron

very easily

Fatigue of Synaptic Transmission.

• When excitatory synapses are repetitively stimulated at a rapid rate

• Number of discharges by the postsynaptic neuron is at first very great

• But the firing rate becomes progressively less in succeeding milliseconds or seconds.

• Fatigue of synaptic transmission.• Protective mechanism

– Against excess neuronal activity •Prevent over excitation

Mechanism Of Fatigue

• Exhaustion or partial exhaustion of the stores

of transmitter substance

• Progressive inactivation of many of the

postsynaptic membrane receptors

• Slow development of abnormal conc. of ions

inside the postsynaptic neuronal cell

Effect of Acidosis or Alkalosis on Synaptic Transmission.

• Neurons are highly responsive to changes in pH

• Alkalosis greatly increases neuronal excitability

– 8.0 often causes cerebral epileptic seizures

• Acidosis greatly depresses neuronal activity;

– a fall in pH from 7.4 to below 7.0

– Severe diabetic or uremic acidosis,

– Coma

Effect of Hypoxia

• Neuronal excitability is also highly dependent on

an adequate supply of oxygen.

• Cessation of oxygen for only a few seconds can

cause complete inexcitability of some neurons

– If Brain’s blood flow is temporarily

interrupted,

– Within 3 to 7 seconds, the person becomes

unconscious.

Effect of Drugs

Stimulants:• Caffeine, Theophylline, and Theobromine,

– found in coffee, tea, and cocoa

• By reducing the threshold for excitation of neurons.

• Strychnine inhibits the action of some inhibitory transmitter substances

Inhibitory • Most Anesthetics increase the neuronal

membrane threshold for excitation

Synaptic delayIs the minimum time required for Is the minimum time required for transmission across the synapsetransmission across the synapse

the synaptic delay 0.5 millisecond. This time is taken by• Discharge of transmitter substance by pre-

synaptic terminal• Diffusion of transmitter to post-synaptic

membrane• Action of transmitter on its receptor• Action of transmitter to membrane permeability• Increased diffusion of Na+ to post-synaptic

potential

Convergence

When many

pre-synaptic neurons

converge on

any single

post-synaptic neuron

Divergence

Axons of most

pre-synaptic neurons

divide into many

branches that

diverge

to end on many post-

synaptic neurons.

Properties of synapse

• Neurotransmitter receptor complex

• One-way conduction

• Summation in Neurons

• Facilitation of Neurons

• Fatigue of Synaptic Transmission

• Effect of Acidosis or Alkalosis on Synaptic Transmission

• Effect of Hypoxia & Drugs

• Synaptic delay

• Convergence & Divergence

Comparison of Synapse and NMJ