Synaptic Transmission in Central Nervous System

Introduction

Synapses in CNS

• Synapses are specialized junctions through which neurons communicate with one another.
• Synaptic transmission enables the transfer of information from one neuron to another within the central nervous system.
• Through synapses, neural signals are relayed to appropriate target neurons and ultimately to effector organs.
• Complex functions of the central nervous system, including information processing, integration, learning, and memory, depend on synaptic activity.
• Synapses exhibit plasticity, allowing their strength and efficiency to change in response to experience and activity.
• Formation of new synaptic connections and modification of existing synapses continue throughout life, contributing to learning and adaptation.

Types of Synapses

The central nervous system contains an enormous number of synapses, with each neuron forming thousands of synaptic connections.

According to Part of the Neurons Involved in the Formation of Synapse

• Synapses are commonly classified according to the neuronal structures involved in their formation.
• The principal types are axodendritic, axosomatic, axoaxonic, and dendrodendritic synapses.

Axodendritic Synapse

In an axodendritic synapse, the axon terminal of the presynaptic neuron forms a connection with a dendrite of the postsynaptic neuron.

This is the most abundant type of synapse in the central nervous system.

The synapse may occur on a dendritic spine, termed an axospinous synapse, or directly on the dendritic shaft.

Axodendritic synapses play an important role in integration of excitatory and inhibitory inputs.

Axosomatic Synapse

• In an axosomatic synapse, the axon terminal of one neuron synapses directly on the cell body of another neuron.
• This type is also common within the central nervous system.
• Because of its proximity to the axon hillock, an axosomatic synapse exerts a strong influence on neuronal firing.

Axoaxonic Synapse

• In an axoaxonic synapse, the axon terminal of the presynaptic neuron forms a synapse with the axon or axon terminal of another neuron.
• These synapses commonly regulate neurotransmitter release through presynaptic inhibition or facilitation.

Dendrodendritic Synapse

• In a dendrodendritic synapse, one dendrite forms a synaptic connection with another dendrite.
• This type is relatively uncommon and is found in specialized regions of the brain, such as the olfactory bulb.
• Among all synaptic types, axodendritic synapses are the most common, followed by axosomatic synapses, whereas dendrodendritic synapses are relatively rare.

According to the Nature of Transmission

• According to the mode of transmission, synapses are classified as chemical, electrical, or mixed synapses.
• In chemical synapses, information is transmitted by the release of neurotransmitters across a synaptic cleft.
• In electrical synapses, impulses pass directly between adjacent cells through gap junctions, permitting rapid signal transmission.
• Mixed synapses possess both chemical and electrical components.

According to the Number of Neurons Involved

• Synapses may also be classified according to the number of neurons involved.
• In one-to-one connections, a single neuron communicates with one target neuron. The neuromuscular junction is a typical example.
• In many-to-one connections, multiple neurons converge onto a single neuron; this is the common pattern in the central nervous system.
• In one-to-many connections, a single neuron diverges and influences multiple target neurons, a pattern frequently observed in the sympathetic nervous system.

Mechanism of Synaptic Transmission

• Synaptic transmission in the central nervous system occurs predominantly through chemical synapses, whereas electrical synapses are relatively uncommon.
• In a chemical synapse, information is transmitted from a presynaptic neuron to a postsynaptic neuron by neurotransmitters.

Functional Anatomy of Synapse

• The specialized region of the axon terminal that releases neurotransmitters is called the presynaptic membrane.
• The receptive surface of the target neuron is known as the postsynaptic membrane.
• The narrow extracellular space separating these membranes is called the synaptic cleft.
• Together, the presynaptic terminal, synaptic cleft, and postsynaptic membrane constitute a functional synapse.
• These structural components ensure precise and regulated communication between neurons.

Presynaptic Axon Terminal

• The presynaptic terminal is the specialized terminal portion of the axon that transmits information to the postsynaptic neuron.
• It commonly ends in a bulbous enlargement known as the synaptic bouton or synaptic knob.
• The presynaptic terminal contains numerous synaptic vesicles and a specialized cytoskeletal framework composed of filamentous proteins.
• Synaptic vesicles store neurotransmitters that are released during synaptic transmission.

Synaptic Vesicles

• Small clear-core vesicles usually contain neurotransmitters such as acetylcholine, gamma-aminobutyric acid, glycine, or glutamate.
• Small dense-core vesicles predominantly contain catecholamines.
• Large dense-core vesicles generally store neuropeptides and other modulatory substances.
• Small synaptic vesicles are concentrated near specialized regions of the presynaptic membrane called active zones.
• Arrival of an action potential triggers exocytosis of neurotransmitters from these vesicles into the synaptic cleft.
• Large dense-core vesicles can release their contents from broader regions of the presynaptic membrane.
• Following neurotransmitter release, small vesicle membranes are retrieved by endocytosis.
• Internalized vesicles fuse with endosomal compartments, where they are recycled.
• Newly formed vesicles bud from endosomes, become refilled with neurotransmitter, and return to the active zone.
• Before neurotransmitter release, vesicles undergo docking and priming, processes that prepare them for rapid exocytosis.

Dense Tufts

• Dense tufts are filamentous protein structures located near synaptic vesicles, particularly within the active zone.
• They assist in vesicle docking and facilitate exocytosis of neurotransmitters.

Active Zone

• The active zone is a specialized region of the presynaptic membrane enriched with proteins and voltage-gated calcium channels.
• Most neurotransmitter release occurs at the active zone following calcium entry.
• Presynaptic terminals also contain numerous mitochondria that supply energy required for synaptic transmission.

Synaptic Cleft

• The synaptic cleft is the narrow space separating the presynaptic and postsynaptic membranes.
• It is approximately 20 to 50 nanometers wide and is filled with extracellular fluid.
• Neurotransmitters released from the presynaptic terminal diffuse across the synaptic cleft to reach receptors on the postsynaptic membrane.

Postsynaptic Membrane

• The postsynaptic membrane is usually located on a dendritic spine but may also be present on the cell body or axon.
• It contains specialized receptors that recognize and bind neurotransmitters.
• A specialized region of the postsynaptic membrane known as the postsynaptic density contains a high concentration of neurotransmitter receptors and associated signaling proteins.
• Binding of neurotransmitters to these receptors initiates electrical or biochemical responses in the postsynaptic neuron.
• Neurotransmitters serve as chemical messengers that transfer information across synapses.
• Activation of numerous postsynaptic receptors generates postsynaptic potentials, which may excite or inhibit the neuron.
• Amplification of synaptic signals occurs because a single presynaptic action potential can activate many postsynaptic receptors simultaneously.

Role of Neurexins

• Neurexins are adhesion proteins located in the presynaptic membrane.
• They bind to complementary proteins on the postsynaptic membrane, thereby establishing stable trans-synaptic connections.
• Neurexins contribute to the structural organization and maintenance of synapses.
• These proteins help align presynaptic neurotransmitter release sites with postsynaptic receptors, ensuring efficient synaptic transmission.
• Extensive genetic diversity and alternative splicing generate numerous neurexin isoforms.
• This molecular diversity is believed to contribute to synaptic specificity, allowing precise formation and maintenance of neural circuits.

Steps of Synaptic Transmission

• Synaptic transmission is the process by which information is transferred from a presynaptic neuron to a postsynaptic neuron across a synapse.
• In chemical synapses, transmission occurs through the release of neurotransmitters from the presynaptic terminal.
• Neurotransmitters bind to receptors on the postsynaptic membrane and generate postsynaptic responses.
• The mechanism of synaptic transmission involves coordinated presynaptic and postsynaptic events.

Presynaptic Mechanisms

• The presynaptic mechanism of synaptic transmission involves a sequence of events that culminates in neurotransmitter release.

Steps in Presynaptic Transmission

• Synaptic vesicles containing neurotransmitters accumulate at specialized regions called active zones.
• Vesicles first undergo docking, during which they attach to the presynaptic membrane.
• Docked vesicles then undergo priming, a process that prepares them for rapid exocytosis.
• Arrival of an action potential at the axon terminal depolarizes the presynaptic membrane.
• Membrane depolarization opens voltage-gated calcium channels located at the active zone.
• Calcium ions enter the presynaptic terminal down their electrochemical gradient.
• The rise in intracellular calcium concentration triggers fusion of synaptic vesicles with the presynaptic membrane.
• Fusion results in exocytosis and release of neurotransmitter into the synaptic cleft.
• Neurotransmitters are released in discrete packets called quanta, a process known as quantal release.
• Released neurotransmitters diffuse across the synaptic cleft and bind to receptors on the postsynaptic membrane.
• The interval between calcium entry and neurotransmitter release is extremely brief, usually less than one millisecond.

Vesicle Recycling

• Following exocytosis, vesicular membrane is retrieved by endocytosis and recycled within the presynaptic terminal.
• Retrieved membrane components are reused for formation of new synaptic vesicles.
• In some synapses, vesicles release neurotransmitter transiently through a fusion pore and are rapidly retrieved without complete collapse into the membrane. This mechanism is termed kiss-and-run exocytosis.

Role of Membrane Proteins

• Efficient neurotransmitter release depends on specialized membrane proteins collectively known as SNARE proteins.
• Synaptobrevin is a vesicle-associated SNARE protein located in the synaptic vesicle membrane.
• Syntaxin and SNAP-25 are target membrane proteins located in the presynaptic membrane.
• Interaction among these proteins mediates vesicle docking, priming, and membrane fusion.
• Additional regulatory proteins, including Rab family guanosine triphosphatases and associated proteins, coordinate vesicle trafficking and exocytosis.

Clinical Significance

• Several neurotoxins impair neurotransmitter release by disrupting SNARE protein function.
• Botulinum toxin cleaves SNARE proteins and prevents fusion of synaptic vesicles with the presynaptic membrane.
• Inhibition of acetylcholine release at the neuromuscular junction by botulinum toxin produces flaccid paralysis.
• Different serotypes of botulinum toxin act on specific SNARE proteins, including SNAP-25, syntaxin, and synaptobrevin.
• Tetanus toxin also interferes with SNARE proteins, particularly synaptobrevin.
• It preferentially inhibits release of inhibitory neurotransmitters such as gamma-aminobutyric acid and glycine within the central nervous system.
• Loss of inhibitory control results in excessive motor neuron activity and produces characteristic spastic paralysis and muscle rigidity.

Postsynaptic Mechanisms

• In the postsynaptic mechanism, neurotransmitters released into the synaptic cleft bind to specific receptors on the postsynaptic membrane.
• Binding of neurotransmitters induces conformational changes in these receptors.
• Receptor activation may directly open ion channels or activate intracellular signaling pathways involving second messengers.
• These processes alter the ionic permeability of the postsynaptic membrane.
• Opening of ion channels permits movement of cations or anions across the membrane.
• Depending on the ions involved, the membrane may undergo depolarization or hyperpolarization.
• Depolarization increases the likelihood of generating an action potential, whereas hyperpolarization reduces neuronal excitability.
• The resulting change in membrane potential is termed a synaptic potential.
• Synaptic potentials constitute the primary signals by which neurons communicate.
• After receptor activation, neurotransmitters are removed from the synaptic cleft to terminate synaptic transmission.
• Removal occurs through enzymatic degradation, diffusion away from the synapse, or reuptake into the presynaptic terminal or surrounding glial cells.
• Efficient neurotransmitter clearance ensures precise regulation of neuronal signaling.

Synaptic Potentials

• Synaptic potentials are graded changes in the postsynaptic membrane potential produced during synaptic transmission.
• They are longer in duration than action potentials and may be either excitatory or inhibitory.

Excitatory Postsynaptic Potential

• An excitatory postsynaptic potential (EPSP) is a depolarizing response that brings the membrane potential closer to threshold.
• For example, if the resting membrane potential changes from –70 mV to –60 mV, an EPSP is generated.
• EPSPs have a short latency, typically about 0.5 milliseconds.
• A single EPSP usually produces a small depolarization of approximately 0.5 to 2 millivolts.
• Although the response generated at an individual synapse is small, simultaneous activation of multiple synapses can produce summation.
• When the summed depolarization reaches threshold, an action potential is initiated in the postsynaptic neuron.
• During an EPSP, the excitability of the postsynaptic neuron increases, making it more responsive to subsequent stimuli.
• Neurotransmitters such as acetylcholine, glutamate, and noradrenaline commonly generate EPSPs.

Ionic Basis

• EPSPs are primarily produced by opening of sodium or calcium channels in the postsynaptic membrane.
• Entry of sodium or calcium ions causes membrane depolarization.
• Closure of potassium channels may also contribute to depolarization by reducing potassium efflux.

Slow EPSP

• Slow EPSPs occur in autonomic ganglia and certain cortical neurons.
• They exhibit a longer latency, usually between 100 and 500 milliseconds, and may persist for several seconds.
• Slow EPSPs are commonly mediated by a reduction in potassium conductance, resulting in prolonged neuronal excitation.

Inhibitory Postsynaptic Potential

• An inhibitory postsynaptic potential (IPSP) is a graded change in membrane potential that hyperpolarizes the postsynaptic neuron.
• Hyperpolarization moves the membrane potential farther from threshold, thereby reducing the likelihood of action potential generation.
• For example, if the resting membrane potential changes from –70 mV to –80 mV, an IPSP is produced.
• Individual IPSPs are usually small, commonly measuring about 0.5 millivolt.
• During an IPSP, the excitability of the postsynaptic neuron decreases, making it less responsive to incoming stimuli.
• Like excitatory postsynaptic potentials, IPSPs are local responses and can undergo temporal and spatial summation.
• Major inhibitory neurotransmitters in the central nervous system include gamma-aminobutyric acid and glycine.
• The inhibitory response reaches a peak within a few milliseconds and then gradually declines.

Ionic Basis

• IPSPs are commonly generated by opening chloride channels in the postsynaptic membrane.
• Entry of chloride ions into the neuron increases membrane negativity and produces hyperpolarization.
• Opening of potassium channels can also generate IPSPs by promoting potassium efflux from the cell.
• Inhibition may additionally occur through closure of sodium or calcium channels, which reduces depolarizing currents.

Slow IPSP

• Slow IPSPs are observed in autonomic ganglia and certain cortical neurons.
• They are generally produced by prolonged increases in potassium conductance.
• Slow IPSPs may persist for several seconds and contribute to sustained neuronal inhibition.

Reversal Potential

• The effect of chloride ion movement depends on the membrane potential relative to the chloride equilibrium potential.
• When the membrane potential equals the chloride equilibrium potential, there is no net chloride movement.
• If the membrane becomes more negative than the chloride equilibrium potential, chloride ions may move outward, reducing membrane negativity. This phenomenon is termed the reversal potential.

Genesis of Action Potential

• A postsynaptic neuron usually receives inputs from numerous presynaptic neurons terminating on its soma and dendrites.
• Excitatory postsynaptic potentials and inhibitory postsynaptic potentials arrive continuously and are integrated by the neuron.
• These graded potentials undergo temporal and spatial summation within the soma and dendritic tree.
• The neuron computes the algebraic sum of all depolarizing and hyperpolarizing influences.
• If the resultant depolarization reaches threshold, typically about 15 mV above the resting membrane potential, an action potential is generated.
• The initial segment of the axon is the usual site of action potential initiation because it possesses the highest density of voltage-gated sodium channels and therefore has the lowest threshold.
• Once initiated, the action potential propagates along the axon toward the nerve terminal (orthodromic conduction).
• Limited backpropagation of action potentials into the soma and dendrites may also occur and can influence synaptic plasticity and neuronal signaling.

Role of Dendrites

• Dendrites are cytoplasmic extensions of the neuronal cell body that serve as the principal receptive region of the neuron.
• They greatly increase the surface area available for synaptic contacts, thereby enhancing integration of excitatory and inhibitory inputs.
• The number and morphology of dendritic spines change during development and are regulated by proteins such as neuroligins.
• Structural modifications of dendritic spines are important for learning, memory, and long-term potentiation.
• Certain dendrites can generate local electrical spikes that influence neuronal signaling.
• Dendritic spines also contain ribosomes and can synthesize proteins locally, thereby modulating synaptic strength and plasticity.

Transmission through an Electrical Synapse

• In electrical synapses, the presynaptic and postsynaptic membranes are closely apposed and connected by gap junctions.
• Gap junctions form low-resistance channels that permit direct passage of ions between adjacent cells.
• Electrical signals pass directly from one neuron to another without the involvement of neurotransmitters.
• Electrical synapses are relatively uncommon in the central nervous system but are important in circuits requiring rapid and synchronized activity.
• Transmission across electrical synapses exhibits very short latency because no chemical mediator is involved.
• Unlike chemical synapses, electrical transmission is often bidirectional, allowing current to flow in either direction.
• Electrical synapses do not significantly amplify or modify signals.
• Consequently, chemical synapses provide greater flexibility for modulation and integration of neuronal activity.
• Transmission through electrical synapses is considerably faster than transmission across chemical synapses.

Properties of Synapses

• Synapses exhibit several physiological properties that regulate neuronal communication and information processing.

Law of Forward Conduction

• In chemical synapses, impulses are transmitted only from the presynaptic neuron to the postsynaptic neuron.
• This unidirectional transmission is known as the law of forward conduction.
• Electrical synapses differ because signal transmission may occur in both directions.

Synaptic Delay

• The interval between arrival of an impulse at the presynaptic terminal and generation of a postsynaptic response is called synaptic delay.
• In chemical synapses, the delay is approximately 0.5 milliseconds.
• Synaptic delay results from calcium entry into the presynaptic terminal, neurotransmitter release, diffusion across the synaptic cleft, and receptor activation.
• Measurement of synaptic delay helps determine whether a neural pathway is monosynaptic or polysynaptic.

Law of Divergence and Convergence

• Divergence refers to transmission of signals from one neuron to multiple postsynaptic neurons.
• Divergent pathways amplify and distribute information to different regions of the nervous system.
• Convergence refers to the projection of multiple presynaptic neurons onto a single postsynaptic neuron.
• Convergent pathways allow integration of information from different sources.
• Convergence and divergence form the physiological basis for summation and facilitation.

Postsynaptic Potentials

• Depolarization of the postsynaptic membrane produces an excitatory postsynaptic potential, which increases neuronal excitability.
• Hyperpolarization of the postsynaptic membrane produces an inhibitory postsynaptic potential, which decreases neuronal excitability.

Synaptic Inhibitions

• Extensive neuronal interconnections in the central nervous system can potentially produce excessive excitation.
• Synaptic inhibition limits unnecessary spread of impulses and maintains neuronal stability.
• Inhibition prevents uncontrolled excitation and ensures coordinated neural activity.
• Synaptic inhibition may occur through direct or indirect mechanisms and can operate as feedback or feedforward inhibition within neural circuits.

Direct and Indirect Inhibitions (Postsynaptic and Presynaptic Inhibitions)

Direct Inhibition

• Direct inhibition or postsynaptic inhibition occurs when inhibitory neurotransmitters act directly on the postsynaptic neuron and generate an inhibitory postsynaptic potential.
• This hyperpolarizes the postsynaptic membrane and decreases the likelihood of action potential generation.
• Direct inhibition commonly involves neurotransmitters such as gamma-aminobutyric acid and glycine.
• Examples include inhibition of anterior horn cells by descending inhibitory pathways and inhibitory interneurons activated by afferents from Golgi tendon organs.
• In these pathways, inhibitory neurotransmitters are released from presynaptic terminals onto the target neuron.

Indirect Inhibition

• Indirect inhibition or presynaptic inhibition occurs when activity in one neuron reduces neurotransmitter release from the terminal of another neuron.
• In this form of inhibition, the inhibitory neuron acts on the presynaptic terminal rather than directly on the postsynaptic neuron.
• The result is a reduction in neurotransmitter release and diminished excitation of the postsynaptic cell.
• Neuronal excitability may also decrease transiently after a previous discharge because the neuron remains in a refractory state or undergoes after-hyperpolarization.
• Prolonged after-hyperpolarization is particularly evident in certain spinal neurons following repetitive firing.

Mechanisms of Presynaptic Inhibition:

• Activation of presynaptic receptors may increase chloride conductance in the presynaptic terminal.
• Increased chloride influx reduces the amplitude of the arriving action potential, thereby decreasing calcium entry and neurotransmitter release.
• Presynaptic receptor activation may also open voltage-gated potassium channels.
• Potassium efflux shortens depolarization and further reduces calcium influx into the terminal.
• In some synapses, neurotransmitter release is directly inhibited through intracellular signaling mechanisms independent of changes in calcium entry.
• Gamma-aminobutyric acid is a major neurotransmitter mediating presynaptic inhibition.
• Activation of GABA_A receptors increases chloride conductance and suppresses transmitter release.
• Activation of GABA_B receptors acts through G proteins to increase potassium conductance and inhibit calcium channels.
• Other neurotransmitters can also produce presynaptic inhibition through similar G protein-mediated effects on calcium and potassium channels.

Feedback and Feedforward Inhibitions

Feedback Inhibition

• Feedback inhibition is a negative feedback mechanism that regulates the activity of spinal motor neurons.
• A collateral branch of a motor neuron activates an inhibitory interneuron within the spinal cord.
• The inhibitory interneuron suppresses further discharge of the same motor neuron, preventing excessive excitation.
• It also inhibits adjacent motor neurons, producing lateral inhibition, which improves the precision and coordination of motor activity.

Feedforward Inhibition

• Feedforward inhibition is a neural mechanism in which excitatory input activates inhibitory neurons that limit downstream neuronal activity.
• In the cerebellum, mossy fibers excite granule cells, whose parallel fibers stimulate Purkinje cells.
• Purkinje cells release gamma-aminobutyric acid, an inhibitory neurotransmitter, reducing the activity of cerebellar output neurons.
• This mechanism refines movement, improves coordination, and prevents excessive motor activity.

Synaptic Facilitation

• Synaptic facilitation is the process in which transmission across a synapse becomes stronger because more neurotransmitter is released from the presynaptic terminal.
• It commonly results from presynaptic facilitation, where the presynaptic action potential is prolonged.
• Prolonged depolarization keeps voltage-gated calcium channels open for a longer duration.
• Increased calcium entry enhances neurotransmitter release into the synaptic cleft.
• Serotonin can promote presynaptic facilitation through axoaxonic synapses.
• It increases intracellular cyclic adenosine monophosphate, leading to phosphorylation and closure of selected potassium channels.
• Delayed repolarization prolongs the action potential, further increasing calcium influx and neurotransmitter release.

Summation

• Summation is the process by which multiple graded postsynaptic potentials combine to produce a larger overall response.
• It occurs because postsynaptic potentials can overlap before they completely disappear.
• Summation plays an essential role in determining whether a neuron reaches the threshold for generating an action potential.
• The two main types are temporal summation and spatial summation.

Temporal Summation

• Temporal summation occurs when a single presynaptic neuron fires repeatedly at a high frequency.
• Successive postsynaptic potentials overlap because each stimulus arrives before the previous response has fully decayed.
• The combined effect increases membrane depolarization and may trigger an action potential.

Spatial Summation

• Spatial summation occurs when two or more presynaptic neurons are activated simultaneously.
• Their postsynaptic potentials combine at the same postsynaptic neuron to produce a greater overall response.
• Simultaneous excitatory inputs increase the likelihood of reaching threshold, whereas simultaneous inhibitory inputs enhance membrane hyperpolarization.
• Excitatory and inhibitory inputs occurring together interact, and the final neuronal response depends on their relative strength, timing, and location.
• Summation enables the nervous system to integrate information from multiple synaptic inputs and generate coordinated neural responses.

Occlusion

• Occlusion occurs when two presynaptic neurons activate overlapping groups of postsynaptic neurons.
• If each presynaptic neuron can independently activate five postsynaptic neurons, simultaneous stimulation may activate only eight instead of ten because some target neurons are shared.
• Occlusion demonstrates the convergence of neural pathways within a neuronal network.

Habituation, Sensitization and Potentiation

Habituation, sensitization, and potentiation are forms of synaptic plasticity that modify the strength of synaptic transmission.

Habituation

• Habituation is a gradual decline in synaptic response during repeated stimulation with a non-harmful stimulus.
• It is mainly caused by reduced neurotransmitter release due to decreased calcium entry or depletion of readily releasable synaptic vesicles.
• Habituation helps the nervous system ignore repetitive, insignificant stimuli.

Sensitization

• Sensitization is a temporary increase in synaptic responsiveness following a painful or noxious stimulus.
• It occurs through presynaptic facilitation, which increases calcium influx into the presynaptic terminal and enhances neurotransmitter release.
• Sensitization improves the response to biologically important or potentially harmful stimuli.

Potentiation

• Potentiation is a sustained increase in synaptic strength that persists after repeated stimulation.
• Post-tetanic potentiation is a short-lasting enhancement caused by residual calcium remaining in the presynaptic terminal after high-frequency stimulation.
• Long-term potentiation is a prolonged increase in synaptic efficacy mediated by activation of N-methyl-D-aspartate receptors, increased postsynaptic calcium entry, and intracellular signaling pathways that strengthen synaptic connections.
• Long-term potentiation is a key cellular mechanism underlying learning and memory.

Synaptic Plasticity

• Synaptic plasticity is the ability of synapses to undergo long-term changes in strength in response to neural activity.
• It enables the nervous system to adapt to experience, learning, and environmental demands.
• These persistent synaptic modifications support learning, memory, and appropriate behavioral responses by altering the efficiency of communication between neurons.

Neurotransmitters

• Neurotransmitters are chemical messengers released from presynaptic nerve terminals that transmit signals to postsynaptic neurons, skeletal muscle fibers, or gland cells.
• They convert electrical impulses into chemical signals, enabling communication across the synaptic cleft.
• Some neuron-derived chemicals enter the bloodstream and function as neurohormones, producing effects on distant target organs.
• A substance is considered a neurotransmitter only if it is synthesized within the neuron, stored in presynaptic vesicles, released in response to an action potential, binds to specific postsynaptic receptors, and is rapidly removed after its action.
• Neurotransmitters are inactivated by enzymatic degradation, reuptake into nerve terminals or surrounding glial cells, or diffusion away from the synapse.
• Rapid removal prevents continuous stimulation and allows accurate transmission of subsequent nerve impulses.
• Chemicals released directly onto target tissues are also referred to as neurosecretions when they act locally outside conventional synapses.
• Neurotransmitters released at the neuromuscular junction mediate communication between motor neurons and skeletal muscle fibers.
• Neuromodulators modify the strength, duration, or effectiveness of synaptic transmission rather than directly generating excitatory or inhibitory responses.
• Together, neurotransmitters and neuromodulators regulate neural communication, coordination, and physiological functions throughout the nervous system.

Classification

• Neurotransmitters are commonly classified according to their chemical structure.
• Major groups include acetylcholine, biogenic amines, amino acids, polypeptides, purines, and gaseous transmitters.
• Biogenic amines include norepinephrine, epinephrine, dopamine, serotonin, and histamine.
• Amino acids include excitatory transmitters such as glutamate and aspartate, and inhibitory transmitters such as gamma-aminobutyric acid and glycine.
• Purines and gases also contribute to neural signaling.

Acetylcholine

Distribution

• Acetylcholine is an important neurotransmitter in both the central and peripheral nervous systems.
• It is released by all autonomic preganglionic neurons, postganglionic parasympathetic neurons, and sympathetic neurons supplying sweat glands.
• It is the neurotransmitter at all neuromuscular junctions, where it initiates skeletal muscle contraction.
• In the central nervous system, acetylcholine is present in the cerebral cortex, basal ganglia, retina, and several other neural pathways.

Synthesis

• It is synthesized in presynaptic terminals from choline and acetyl coenzyme A by the enzyme choline acetyltransferase.
• After synthesis, it is stored in synaptic vesicles and released by calcium-dependent exocytosis when an action potential reaches the nerve terminal.
• Released acetylcholine binds to specific cholinergic receptors on the postsynaptic membrane to produce its physiological effects.

Receptors

• Cholinergic receptors are divided into two major types: nicotinic receptors and muscarinic receptors.

Nicotinic Receptors

• Nicotinic receptors are ligand-gated ion channels that mediate rapid excitatory synaptic transmission.
• They are present at the neuromuscular junction, autonomic ganglia, adrenal medulla, and several regions of the central nervous system.
• Each nicotinic receptor consists of five protein subunits arranged around a central ion channel.
• Binding of acetylcholine opens the channel, allowing mainly sodium ions to enter and potassium ions to leave, producing membrane depolarization.
• Neuronal nicotinic receptors are also permeable to calcium ions, which influence neurotransmitter release and intracellular signaling.
• The subunit composition differs between skeletal muscle, autonomic ganglia, and the brain, producing receptors with distinct physiological properties.

Muscarinic Receptors

• Muscarinic receptors are G protein-coupled receptors that produce slower and longer-lasting cellular responses.
• Five subtypes, M1, M2, M3, M4, and M5, have been identified.
• They are widely distributed in the brain, cardiac muscle, smooth muscle, exocrine glands, and other visceral organs.
• Activation of muscarinic receptors regulates ion channels and intracellular second messenger systems, producing tissue-specific responses.
• Atropine competitively blocks all muscarinic receptor subtypes and is widely used in clinical practice.
• After release into the synaptic cleft, acetylcholine is rapidly hydrolyzed into choline and acetate by the enzyme acetylcholinesterase.
• Rapid enzymatic degradation terminates synaptic transmission and prevents continuous stimulation of cholinergic receptors.
• Choline is actively transported back into the presynaptic terminal by a high-affinity transporter.
• The recycled choline is reused for the synthesis of new acetylcholine molecules, ensuring efficient neurotransmission.
• Rapid synthesis, release, receptor activation, enzymatic degradation, and choline recycling together maintain precise cholinergic signaling throughout the nervous system.

Catecholamines

• Catecholamines include epinephrine, norepinephrine, and dopamine, which function as neurotransmitters and, in some tissues, as hormones.
• They are widely distributed in the central nervous system, spinal cord, and peripheral nervous system.
• Norepinephrine is the principal neurotransmitter released by most postganglionic sympathetic neurons, whereas epinephrine is mainly secreted by the adrenal medulla into the bloodstream.
• Catecholamines are stored in dense-core vesicles and released by calcium-dependent exocytosis in response to nerve stimulation.
• After release, they bind to specific receptors on target cells to produce their physiological effects.
• Epinephrine and norepinephrine act through adrenergic receptors, which are G protein-coupled receptors.
• Adrenergic receptors are classified into alpha and beta types, with alpha₁, alpha₂, beta₁, beta₂, and beta₃ subtypes.
• Alpha₂ receptors are also present on presynaptic nerve terminals, where they reduce further norepinephrine release through negative feedback.
• Catecholamines are inactivated by monoamine oxidase, catechol-O-methyltransferase, and neuronal reuptake, ensuring precise regulation of neurotransmission.

Dopamine

• Dopamine is an important neurotransmitter in several brain pathways involved in movement, motivation, reward, and endocrine regulation.
• Dopaminergic neurons of the nigrostriatal pathway are essential for normal voluntary motor control.
• Five dopamine receptor subtypes, D1 to D5, have been identified, and all belong to the G protein-coupled receptor family.
• Reduced dopaminergic activity in the nigrostriatal pathway contributes to Parkinson disease, whereas excessive dopamine signaling, particularly through D2 receptors, is associated with psychotic disorders.
• Dopamine receptor antagonists, especially those targeting D2 receptors, are widely used in the treatment of schizophrenia.

Gamma Aminobutyric Acid

Gamma-aminobutyric acid is the principal inhibitory neurotransmitter in the brain and is also present in the retina.

Synthesis and Metabolism

• It is synthesized from glutamate by the enzyme glutamate decarboxylase.
• Gamma-aminobutyric acid is mainly metabolized by gamma-aminobutyric acid transaminase, producing metabolites that enter the citric acid cycle.

Receptors

• Three receptor types have been identified: gamma-aminobutyric acid A, gamma-aminobutyric acid B, and gamma-aminobutyric acid C receptors.
• Gamma-aminobutyric acid A and gamma-aminobutyric acid C receptors are ligand-gated chloride ion channels, whereas gamma-aminobutyric acid B receptors are G protein-coupled receptors.
• Activation of gamma-aminobutyric acid A and gamma-aminobutyric acid C receptors increases chloride ion influx, causing neuronal hyperpolarization.

Functions

• Activation of gamma-aminobutyric acid B receptors increases potassium ion efflux, decreases calcium ion entry, and reduces cyclic adenosine monophosphate production, thereby suppressing neurotransmitter release.
• These actions generate inhibitory postsynaptic potentials and reduce neuronal excitability.
• Gamma-aminobutyric acid plays an essential role in regulating motor control, sensory processing, emotional responses, sleep, and seizure threshold.
• Reduced gamma-aminobutyric acid activity has been associated with epilepsy, anxiety disorders, and several neurodegenerative conditions.
• Benzodiazepines enhance the activity of gamma-aminobutyric acid A receptors, increasing chloride ion conductance and producing sedative, anxiolytic, anticonvulsant, and muscle relaxant effects.
• Barbiturates and alcohol also enhance inhibitory neurotransmission through gamma-aminobutyric acid A receptor-mediated chloride channels, although by different pharmacological mechanisms.
• Neurosteroids, including progesterone metabolites, can positively modulate gamma-aminobutyric acid A receptors, contributing to sedative and anesthetic effects.
• Balanced gamma-aminobutyric acid signaling is essential for maintaining normal neuronal activity and preventing excessive excitation within the central nervous system.

Glycine

• Glycine is an important neurotransmitter that functions mainly as an inhibitory neurotransmitter in the spinal cord and brainstem.
• Glycine receptors are ligand-gated chloride ion channels composed of alpha and beta subunits.
• Activation of these receptors increases chloride ion influx, producing inhibitory postsynaptic potentials and reducing neuronal excitability.
• In certain brain regions, glycine also acts as a co-agonist at N-methyl-D-aspartate receptors, facilitating glutamate-mediated excitatory neurotransmission.
• This interaction contributes to normal synaptic transmission and pain processing in the dorsal horn of the spinal cord.

Neurons causing direct inhibition

Inhibitory interneurons may release glycine, gamma-aminobutyric acid, or both neurotransmitters to regulate neuronal activity.

Glutamate

• Glutamate is the principal excitatory neurotransmitter in the central nervous system and mediates most fast excitatory synaptic transmission.
• It is synthesized from metabolic intermediates and stored in synaptic vesicles before release.
• After release, glutamate is rapidly taken up by astrocytes, converted to glutamine, and transported back to neurons for resynthesis into glutamate.
• This glutamate–glutamine cycle maintains neurotransmitter availability and prevents excessive extracellular glutamate accumulation.
• Excessive glutamate activity can cause excitotoxicity, leading to neuronal injury in conditions such as stroke, traumatic brain injury, and certain neurodegenerative disorders.
• Balanced actions of glycine and glutamate are essential for normal motor control, sensory processing, learning, memory, and pain modulation.

Serotonin

• Serotonin, also called 5-hydroxytryptamine, is an important neurotransmitter in the central nervous system, enteric nervous system, and retina.
• It is synthesized from the amino acid tryptophan by hydroxylation followed by decarboxylation.
• Serotonin acts through multiple receptor families, most of which are G protein-coupled receptors, whereas the 5-hydroxytryptamine type 3 receptor is a ligand-gated ion channel.
• Serotonergic pathways participate in pain modulation, mood regulation, sleep, appetite, learning, and autonomic functions.
• Descending serotonergic pathways from the brainstem contribute to endogenous analgesia by suppressing pain transmission in the spinal cord.
• Altered serotonin signaling is associated with depression, anxiety disorders, migraine, and several gastrointestinal disorders.

Histamine

• Histamine functions as both a neurotransmitter and a locally acting chemical mediator.
• Histaminergic neurons are mainly located in the hypothalamus and project widely throughout the brain.
• Histamine acts through H1, H2, H3, and H4 receptors, although H4 receptors are primarily expressed in immune cells rather than the central nervous system.
• Within the brain, histamine regulates wakefulness, attention, appetite, and cognitive function.
• In peripheral tissues, histamine promotes smooth muscle contraction, increases vascular permeability, causes arteriolar vasodilation, and stimulates gastric acid secretion.
• These diverse actions make serotonin and histamine essential regulators of neural communication and multiple physiological processes.

Substance P and Other Tachykinins

• Substance P is a tachykinin neuropeptide widely distributed in the central nervous system, peripheral nerves, and gastrointestinal tract.
• Other members of the tachykinin family include neurokinin A and neurokinin B.
• Tachykinins act through NK-1, NK-2, and NK-3 receptors, which are predominantly G protein-coupled receptors.
• Substance P primarily binds to NK-1 receptors, activating intracellular signaling pathways involving phospholipase C.

Functions of Substance P

• It is an important neurotransmitter in pain transmission, particularly within the dorsal horn of the spinal cord.
• Substance P also participates in neuroendocrine regulation, intestinal peristalsis, and local inflammatory responses through the axon reflex.
• In the basal ganglia, it functions as a co-transmitter with dopamine in motor pathways.
• Excessive substance P signaling has been linked to chronic pain, inflammation, nausea, and mood disorders.
• NK-1 receptor antagonists are used clinically to prevent chemotherapy-induced nausea and vomiting.

Calcitonin-Gene Related Peptide

• Calcitonin gene-related peptide is a neuropeptide present in two forms: alpha and beta.
• The alpha form is abundant in primary sensory neurons, blood vessels, the thalamus, and selected brain pathways, whereas the beta form is mainly found in the gastrointestinal tract.
• Calcitonin gene-related peptide is commonly co-released with substance P from sensory nerve endings.
• In the spinal cord, it modulates pain transmission and contributes to central sensitization.
• It is one of the most potent physiological vasodilators, increasing blood flow through relaxation of vascular smooth muscle.
• Excessive calcitonin gene-related peptide activity plays an important role in the pathophysiology of migraine, and calcitonin gene-related peptide antagonists are effective preventive and therapeutic agents.

Neuropeptide Y

• Neuropeptide Y is a 36-amino acid peptide widely distributed in the brain and autonomic nervous system.
• It is highly expressed in the hypothalamus, where it strongly stimulates appetite and reduces energy expenditure.
• Neuropeptide Y acts through Y receptors, which are G protein-coupled receptors, to regulate food intake, stress responses, cardiovascular function, and autonomic activity.

Purines and Pyrimidines

Purines, including adenosine and adenosine triphosphate, also function as neurotransmitters and neuromodulators.

Adenosine

• Adenosine generally suppresses neuronal activity and acts as a vasodilator in many vascular beds.
• It acts through four G protein-coupled receptor subtypes: A1, A2A, A2B, and A3.
• Caffeine and theophylline increase alertness by competitively blocking adenosine receptors in the central nervous system.
• Adenosine also limits excessive neuronal excitation and provides protection during ischemia by reducing neurotransmitter release.

ATP

• Adenosine triphosphate functions as a neurotransmitter in both the central and autonomic nervous systems.
• It acts through P2X ligand-gated ion channels and P2Y G protein-coupled receptors.
• Adenosine triphosphate participates in sensory transmission, autonomic signaling, inflammation, and neuron-glia communication.
• P2X receptors in the dorsal horn of the spinal cord contribute to the transmission of nociceptive information.
• Together, these neuropeptides and purinergic transmitters regulate pain, vascular tone, metabolism, autonomic function, and neural communication.

Nitric Oxide

• Nitric oxide is a gaseous signaling molecule produced from arginine by the enzyme nitric oxide synthase.
• In blood vessels, it causes vasodilation by relaxing vascular smooth muscle.
• In the brain, nitric oxide acts as a retrograde messenger and contributes to long-term potentiation, synaptic plasticity, learning, and memory.

Co-transmitters

• Co-transmitters are chemicals released together with classical neurotransmitters to modify synaptic transmission.
• They enhance, prolong, or regulate the actions of primary neurotransmitters, allowing more precise neural communication.