SYNAPTIC TRANSMISSION

FAiq Group

Introduction

• Impulses are transmitted from one nerve cell to another cell at synapses via chemical means
• Synapsis are the junctions where the axon or some other portion of one cell (the presynaptic cell) terminates on the dendrites, soma, or axon of another neuron or, in some cases, a muscle or gland cell (the postsynaptic cell )
• In a synapse, the terminal of a presynaptic cell is connected from the postsynaptic cell via synaptic cleft
• An impulse in the presynaptic axon causes secretion of a chemical that diffuses across the synaptic cleft and binds to receptors on the surface of the postsynaptic cell

• This triggers events that open or close channels in the membrane of the postsynaptic cell leading to either its excitation or inhibition
• Transmission from nerve to muscle resembles�chemical synaptic transmission from one neuron to another
• The neuromuscular junction, the specialized area where a motor nerve terminates on a skeletal muscle fiber, is the site of a stereotyped transmission process
• The contacts between autonomic neurons and smooth and cardiac muscle are less specialized, and transmission in these locations is a more diffuse process

SYNAPTIC TRANSMISSION:�FUNCTIONAL ANATOMY

• The anatomic structure of synapses varies considerably in the different parts of the mammalian nervous system
• The ends of the presynaptic fibers are generally enlarged to form terminal boutons or synaptic knobs
• In the cerebral and cerebellar cortex, endings are commonly located on dendrites and frequently on dendritic spines
• In some instances, the terminal branches of the axon of the presynaptic neuron form a basket or net around the soma of the postsynaptic cell (eg, basket cells of the cerebellum).

• In other locations, they intertwine with the dendrites of the postsynaptic cell (eg, climbing fibers of the cerebellum) or end on the dendrites directly (eg, apical dendrites of cortical pyramidal cells)
• Some end on axons of postsynaptic neurons (axoaxonal endings)
• On average, each neuron divides to form over 2000 synaptic endings; so it is estimated that human brain(10¹¹ neurons)contains about 2 × 10¹⁴ synapses
• Obviously, therefore, communication between neurons is extremely complex
• Synapses are dynamic structures, increasing and decreasing in complexity and number with use and experience

• It has been calculated that in the cerebral cortex, 98% of the synapses are on dendrites and only 2% are on cell bodies
• In the spinal cord, the proportion of endings on dendrites is less; there are about 8000 endings on the dendrites of a typical spinal neuron and about 2000 on the cell body, making the soma appear encrusted with endings

FUNCTIONS OF SYNAPTIC ELEMENTS

• A synaptic cleft, which separates the presynaptic terminal of a neuron with the postsynaptic membrane of the other cell, is 20–40 nm wide
• Across the synaptic cleft are many neurotransmitter receptors in the postsynaptic membrane, and usually a postsynaptic thickening called the postsynaptic density
• The postsynaptic density is an ordered complex of specific receptors, binding proteins, and enzymes�induced by postsynaptic effects

• Inside the presynaptic terminal are many mitochondria, as well as many membrane-enclosed vesicles, which contain neurotransmitters
• There are three kinds of synaptic vesicles: small, clear synaptic vesicles that contain ACh, glycine, GABA, or glutamate; small vesicles with a dense core that contain catecholamines; and large vesicles with a dense core that contain neuropeptides
• The vesicles and the proteins contained in their walls are synthesized in the neuronal cell body and transported along the axon to the endings by�fast axoplasmic transport

• These vesicles fuse with the cell membrane and�release transmitters through exocytosis and are then recovered by endocytosis to be refilled locally
• In some instances, they enter endosomes and are budded of the endosome and refilled, starting the cycle over again
• More commonly, however, the synaptic vesicle discharges its contents through a small hole in the�cell membrane, then the opening reseals rapidly and the main vesicle stays inside the cell (kiss-and-run discharge)
• In this way, the full endocytotic process is short-circuited

• The large dense-core vesicles are located throughout the presynaptic terminals and release their neuropeptide contents by exocytosis from all parts of the terminal
• Whereas the small vesicles are located near the synaptic cleft and fuse to the membrane, quickly emptying their contents very rapidly into the cleft at areas of membrane thickening called active zones
• The active zones contain many proteins and rows of Ca2+ channels
• The release of neurotransmitters from the presynaptic terminal begins with the invasion of the action potential into the axon terminal

• The depolarization of the terminal by the action potential causes the activation of voltage-gated Ca²⁺ channels
• The electrochemical gradients for Ca²⁺ result in forces that drive Ca²⁺ into the terminal
• This increase in intracellular ionized calcium causes a fusion of vesicles, containing neurotransmitters,�with the presynaptic membrane at active zones
• The neurotransmitters are then released into the cleft by exocytosis
• Increasing the amount of Ca²⁺ that enters the terminal increases the amount of transmitter released into the synaptic cleft

• The number of transmitter molecules released by�any one exocytosed vesicle is called a quantum, and the total number of quanta released when the synapse is activated is called the quantum content
• Under normal conditions, quanta are fixed in size but quantum content varies, particularly with the amount of Ca2 that enters the terminal
• In addition, the transmitter must be released close to the postsynaptic receptors to be effective on the postsynaptic neuron
• This orderly organization of the synapse depends in part on neurexins, proteins bound to the membrane of the presynaptic neuron that bind neurexin receptors in the membrane of the postsynaptic neuron

• The way in which the entry of Ca²⁺ leads to the fusion of the vesicles with the presynaptic membrane is still being elucidated
• The vesicles involve the v-snare protein synaptobrevin in the vesicle membrane locking with the t-snare protein syntaxin in the cell membrane; a multiprotein complex regulated by small GTPases such as Rab3
• These proteins dock and bind the vesicles to the presynaptic terminal membrane
• To complete the process begun by Ca²⁺ entry into the nerve terminal, the docked and bound vesicles must fuse with the membrane and create a pore through which the transmitter may be released into the synaptic cleft

• The vesicle membrane is then removed from the terminal membrane and recycled within the nerve terminal
• Several deadly toxins that block neurotransmitter release are zinc endopeptidases that cleave and hence inactivate proteins in the fusion-exocytosis complex
• Examples are tetanus toxin and botulinum toxin which exert their devastating effects on the nervous system by disrupting the function of SNARES, preventing synaptic transmission
• Exposure to these toxins can be fatal because the�failure of neurotransmission (NT) between neurons and the muscles involved in breathing results in respiratory failure

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Excitatory & Inhibitory Postsynaptic Potentials

• Once released into the synaptic cleft, NT molecules exert their actions by binding to receptors in the�postsynaptic membrane
• Receptors are either direct ion channel proteins or G-coupled proteins linked with 2^nd messenger
• When a transmitter binds to its receptor, membrane�conductance changes occur, leading to depolarization or hyperpolarization
• An increase in membrane conductance to Na⁺ depolarizes the membrane
• An increase in membrane conductance that permits the efflux of K ⁺ or the influx of Cl^- hyperpolarizes the membrane

• In some cases, membrane hyperpolarization can occur when a decrease in membrane conductance reduces the influx of Na⁺
• The transmission of impulse from one neuron to the next neuron or the other cell occurs with a small delay of 0.5ms called synaptic delay
• A single stimulus does not lead to a propagated AP in the postsynaptic neuron; rather, produces a transient partial depolarization or hyperpolarization
• If depolarization results as a result of a single impulse, it reaches its peak 11.5 ms later and then declines exponentially
• During this potential, the excitability of the neuron to other stimuli is ↑, and consequently the potential is called an excitatory postsynaptic potential (EPSP)

Mechanism of EPSP

EPSP is a local potential (response) in the synapse

• Similarly, If hyperpolarization results as a result of an inhibitory impulse, it reaches its peak 11.5 ms later and then declines exponentially
• During this potential, the excitability of the neuron to other stimuli is decreased; consequently, it is called an inhibitory postsynaptic potential (IPSP)
• The membr. depolarizations and hyperpolarizations are integrated or summated and can result in activation or inhibition of the postsynaptic neuron
• Alterations in the MP, that occur in the postsynaptic neuron, initially take place in the dendrites and the soma as a result of the activation of afferent inputs

Synaptic Inhibition

• Inhibition of synaptic transmission is classified into five types:
• 1. Postsynaptic or direct inhibition
• 2. Presynaptic or indirect inhibition
• 3. Negative feedback or Renshaw cell inhibition
• 4. Feedforward inhibition
• 5. Reciprocal inhibition��

• 1. Postsynaptic or Direct Inhibition:
• Occurs due to the release of an inhibitory NT from presynaptic terminal, e.g., GABA, dopamine and glycine
• These inhibitory NT either open K+ channels or Cl- channels leading to hyperpolarization and thus cause postsynaptic inhibition
• 2. Presynaptic or Indirect Inhibition:
• Occurs due to the failure of presynaptic axon terminal to release sufficient quantity of excitatory NT substance
• Presynaptic inhibition is mediated by axoaxonal�synapses

Mechanism of IPSP

• Prominent in spinal cord and regulates the propaga- -tion of information to higher centers in brain
• Normally, during synaptic transmission, AP reaching the presynaptic neuron produces development of EPSP in the postsynaptic neuron
• But, in spinal cord, a modulatory neuron called presynaptic inhibitory neuron forms an axoaxonic synapse with the presynaptic neuron
• The inhibitory neuron inhibits the presynaptic neuron and ↓ the magnitude of AP in presynaptic neuron
• The smaller action potential reduces calcium influx
• This in turn ↓ the quantity of NT released by presynaptic neuron.
• The resulting magnitude of EPSP in postsynaptic neuron is ↓ resulting in synaptic inhibition

• 3. Renshaw Cell or Negative Feedback Inhibition:
• Renshaw cells are small motor neurons present�in anterior gray horn of spinal cord
• Anterior nerve root consists of nerve fibers, which�leave the spinal cord
• These nerve fibers arise from α-­motor neurons in anterior gray horn of the spinal cord and reach the effector organ, muscles
• Some of the fibers called collaterals fibers terminate on Renshaw cells instead of leaving the spinal cord
• When motor neurons send motor impulses, some of the impulses reach the Renshaw cell by passing through collaterals

• Now, the Renshaw cell is stimulated
• In turn, it sends inhibitory impulses to α­-motor neurons so that, the discharge from motor neurons is reduced
• Renshaw cell inhibition, thus, represents a -tive feedback mechanism
• A Renshaw cell may be�supplied by more than one α­-motor neuron collateral and it may synapse on many motor neurons

• 4. Feedforward Inhibition:
• Feedforward synaptic (-) occurs in cerebellum and it controls the neuronal activity in cerebellum
• In this part of the brain, stimulation of basket cells produces IPSPs in the Purkinje cells by releasing GABA
• However, the basket cells and the Purkinje cells are excited by the same parallel-fiber excitatory input
• 5. Reciprocal Inhibition:
• Inhibition of antagonistic muscles when a group of�muscles are activated is called reciprocal inhibition
• This is due to impulses in afferent fiber which cause EPSPs in the postsynaptic motor neurons (PSMN) and IPSPs in PSMN supplying antagonistic muscles

Presynaptic Facilitation

• Produced when the action potential is prolonged and the Ca2+ channels are open for a longer period
• The molecular events responsible for the production of presynaptic facilitation mediated by serotonin in the sea snail Aplysia have been worked out in detail
• Serotonin released at an axoaxonal ending ↑ intra-neuronal cAMP levels, and the resulting phospho- -rylation of one group of K+ channels closes the channels, slowing repolarization and prolonging the action potential

SUMMATION

• Summation is the fusion of effects or progressive increase in the excitatory postsynaptic potential in post synaptic neuron when many presynaptic excitatory terminals are stimulated simultaneously (Spatial Summation) or when single presynaptic terminal is stimulated repeatedly (Temporal Summation)
• Increased EPSP triggers the axon potential in the initial segment of axon of postsynaptic neuron�

CONVERGENCE AND DIVERGENCE

• CONVERGENCE: The process by which many presynaptic neurons terminate on a single postsynaptic neuron
• DIVERGENCE:The process by which one presynaptic�neuron terminates on many postsynaptic neurons����

FATIGUE

• During continuous muscular activity, synapse becomes the seat of fatigue
• Fatigue at synapse is due to the depletion of neurotransmitter substance, acetylcholine
• Depletion of acetylcholine occurs because of two factors:
• i. Soon after the action, acetylcholine is destroyed�by acetylcholinesterase
• ii. Due to continuous action, new acetylcholine is�not synthesized

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, after entering the muscle belly, normally branches and stimulates from three to�several hundred skeletal muscle fibers
• Each nerve ending makes a junction, called the NMJ, with the muscle fiber near its midpoint
• The AP initiated in the muscle fiber by the nerve signal travels in both directions toward the muscle fiber ends

Physiologic Anatomy of the NMJ�—The Motor End Plate.

• Terminal branch of nerve fiber, when comes close to muscle fiber, loses the myelin sheath and divides into a number of terminal boutons
• These terminal boutons contains mitochondria and synaptic vesicles which contain the NT, Ach
• The Ach is synthesized by mitochondria present in the axon terminal and stored in the vesicles
• Mitochondria contain ATP, which is the source of energy for the synthesis of acetylcholine
• The bouton invaginates inside the muscle fiber and forms a depression, which is known as synaptic trough or synaptic gutter

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• At the invagination, the muscle membrane is thickened to form the motor end plate
• The entire structure is covered by one or more Schwan cells that insulate it from the surrounding fluids
• The space between the terminal and the fiber membrane is called the synaptic space or synaptic cleft and is 20 to 30 nanometers wide
• At the bottom of the gutter are numerous smaller folds of the muscle membrane called subneural clefts, which greatly increase the surface area at which the synaptic transmitter can act
• Synaptic cleft contains large quantities of the enzyme acetylcholinesterase (AChE) which destroys ACh a few ms after it has been released from the synaptic vesicles

SEQUENCE OF EVENTS�DURING TRANSMISSION

• The sequence of events during impulse transmission at NMJ are similar to those at neuron-to-neuron synapses
• The impulse arriving in the end of the motor neuron increases the permeability of its endings to Ca²⁺
• Ca²⁺ enters the endings and triggers a marked ↑ in exocytosis of the ACh-containing synaptic vesicles
• The ACh diffuses to nicotinic (N_M ) receptors that are concentrated at the tops of the junctional folds of the membrane of the motor end plate

• Binding of ACh to these receptors ↑ the Na⁺ and K ⁺ conductance, and the resultant influx of Na ⁺ produces a depolarizing potential, the end plate potential
• The current sink created by this local potential depolarizes the adjacent muscle membrane to its firing level
• APs are generated on either side of the end plate and are conducted away from the end plate in both directions along the muscle fiber
• The muscle AP, in turn, initiates muscle contraction
• ACh is then removed from the synaptic cleft by AChE