Synaptic Transmitters and Neuronal Pools

Synaptic Transmitters, Transmission Signals, and Neuronal Pools Overview

• There are approximately 50 substances identified as synaptic transmitters.
• There are two broad categories: small-molecule, rapidly acting neurotransmitters and neuropeptides (slowly acting).
• Small-molecule neurotransmitters work quickly and are involved in immediate synaptic transmission.
• Neuropeptides are larger molecules, tend to have a prolonged effect, and are often involved in long-term neuronal regulation.

Chemical Synaptic Transmitters

• Chemical synaptic transmitters are divided into two classes: small-molecule, rapidly acting neurotransmitters and neuropeptides.

Small-Molecule, Rapidly Acting Neurotransmitters

• Synthesized in the cytosol of the presynaptic terminal.
• Stored in vesicles, which are filled via active transport mechanisms.
• An action potential reaches the presynaptic terminal, triggering fusion with the presynaptic membrane.
• Neurotransmitter molecules are released into the synaptic cleft and they bind to receptors on the postsynaptic neuron.
• The binding of neurotransmitters to receptors can alter ion conductance, which lead to either depolarization (excitatory effect) by increased sodium conductance, or hyperpolarization (inhibitory effect) by increased potassium or chloride conductance.
• After neurotransmitter release to the synaptic cleft, vesicles are recycled.

Recycling Mechanism

• Vesicles contain enzymes and transport proteins necessary for neurotransmitter synthesis and reloading.

Types of Small-Molecule Transmitters

• Includes acetylcholine (ACh), noradrenaline (norepinephrine), dopamine, serotonin (5-HT), gamma-aminobutyric acid (GABA), glutamate, glycine, and nitric oxide (NO).

Acetylcholine (ACH)

• Synthesized in the presynaptic terminal through the reaction of Acetyl coenzyme A (Acetyl-CoA) + Choline → Acetylcholine (ACH) catalyzed by the enzyme choline acetyltransferase.
• Once released into the synaptic cleft, ACh is rapidly broken down by the enzyme Acetylcholinesterase (ACHE) into Acetate and Choline.
• Choline is then recycled back into the presynaptic neuron.

Functions of Acetylcholine

• Mainly excitatory, but has some inhibitory roles.
• Acts in both the Central Nervous System (CNS) and Peripheral Nervous System (PNS).

Functions in CNS

• Cognitive functions.

Functions in PNS

• Autonomic Nervous System:
  • Preganglionic parasympathetic and sympathetic neurons.
  • Postganglionic parasympathetic neurons.
  • Some postganglionic sympathetic neurons.
• Somatic Nervous System: motor neurons that control skeletal muscles.

Clinical Relevance

• Alzheimer's Disease relates to damage of ACh-secreting neurons.
• Myasthenia Gravis is an autoimmune disorder where the number of ACh receptors is reduced, leading to generalized skeletal muscle weakness.

Noradrenaline (Norepinephrine)

• Primarily excitatory.

CNS Function

• In some regions.

PNS Function

• Main neurotransmitter of postganglionic sympathetic neurons.
• Excites some organs and inhibits others, depending on receptor type.

Drug Effects

• Cocaine increases noradrenaline release, leading to overstimulation of postganglionic neurons.

Dopamine

• Usually inhibitory activating inhibitory receptors which open K+ and Ca2+ channels.
• Most frequent catecholamine in the CNS.

Functions

• Mood regulation.
• Memory and learning.
• Motivation.

Clinical Relevance

• Parkinson's Disease involves the degeneration of dopamine-producing neurons, leading to motor impairment.
• Schizophrenia is correlated with high dopamine levels.

Serotonin (5-HT)

• Mainly inhibitory.

Functions

• Inhibits pain pathways in the spinal cord.
• Regulates mood, appetite, learning, memory, and sleep.

Clinical Relevance

• High serotonin levels are linked to schizophrenia.
• SSRIs (Selective Serotonin Reuptake inhibitors) prevent serotonin reuptake, increasing its duration in the synaptic cleft and used as antidepressants.

Gamma-Aminobutyric Acid (GABA)

• Main inhibitory neurotransmitter in the CNS which opens K+ and Cl- channels, which reduces excitability

Clinical Relevance

• Drugs increasing GABA function help treat epilepsy and prevent seizure.

Glutamate

• Main excitatory neurotransmitter in the brain.
• Enhances learning and memory.
• Opens Na+ channels, causing an excitatory effect.

Clinical Relevance

• Excess glutamate can cause seizures.
• Glutamate blockers are being developed to prevent convulsions.

Glycine

• Main inhibitory neurotransmitter in the spinal cord.
• Opens Cl- channels to cause hyperpolarization.

Clinical Relevance

• Strychnine Poisoning blocks glycine receptors, causing motor neurons to become hyperexcitable, leading to convulsions, respiratory failure, and death.

Nitric Oxide (NO)

• A non-traditional neurotransmitter that is not stored in vesicles.
• Synthesized on demand and Diffuses through membranes instead of binding to receptors.

Functions

• Alters intracellular metabolic functions to modulate neuronal excitability.

Neurotransmitter Removal

• Once neurotransmitters are released, they must be cleared from the synaptic cleft.
• Two primary mechanisms exist which are reuptake by presynaptic neuron and enzymatic degradation.
• SSRIs prevent serotonin reuptake, prolonging its effect.
• ACh is broken down by acetylcholinesterase (ACHE).

Neuropeptides - Slowly Acting Neurotransmitters

• Include peptides and small proteins.
• Have slow, prolonged effects.
• They are synthesized differently from small-molecule neurotransmitters.

Synthesis

• Synthesized in the cytosol by ribosomes.
• Processed in the endoplasmic reticulum and Golgi apparatus.
• Stored in small transmitter vesicles.

Release

• Once released, vesicles are destroyed (autolyzed) and NOT recycled.
• Much smaller quantities released compared to small-molecule neurotransmitters.
• Effect is much more prolonged (can last days, months, years).

Characteristics

• Can cause long-term closure of calcium channels, Activation of cell gene transcription, and Changes in the number of excitatory or inhibitory receptors.
• Can cause prolonged changes such as long-term memory.

Function

• Usually inhibitory.
• Widely distributed in the CNS and PNS.

Examples

• Endorphins and Enkephalins where Opioids (eg, morphine) bind to endorphin receptors to reduce pain perception.
• Substance P is also usually excitatory and involved in pain transmission in the brain where Morphine inhibits the release of Substance P and blocks pain transmission.

Synaptic Transmission

• The time it takes for a signal to be transmitted from a presynaptic neuron to a postsynaptic neuron is called synaptic delay.
• Minimal time required: 0.5 milliseconds.

Steps contributing to synaptic delay

• Neurotransmitter release from presynaptic terminal.
• Neurotransmitter diffusion across the synaptic cleft.
• Binding to postsynaptic membrane receptors.
• Activation of receptor-mediated processes such as Sodium influx and action potential initiation.

Large Motor Neurons

• Large motor neurons located in the anterior horns of the spinal cord have a resting membrane potential of -65 mV.
• These neurons follow the same basic principles, but quantitative differences exist.

Membrane Potential Differences

• Large peripheral nerve fibers have a resting membrane potential of -90 mV while neurons have a resting membrane potential of -65 mV.
• Higher resting membrane potential (-65 mV) for neurons.
• This difference allows for both excitatory and inhibitory control of excitability.

Fatigue of Synaptic Transmission

• When a synapse is rapidly stimulated, its ability to transmit signals decreases.
• Initially, a large number of postsynaptic discharges occur but with continued stimulation, the response progressively diminishes.

Causes of Fatigue

• Depletion of neurotransmitter
• Inactivation of postsynaptic membrane receptors
• Abnormal ion concentrations in the postsynaptic neuron
• Fatigue is a protective mechanism against excessive neuronal activity and Prevents overexcitation in conditions such as epileptic seizures.

Effects of pH

• Neuronal excitability requires a narrow pH rang

Effect of Alkalosis (Increased pH)

• If arterial blood pH increases from 7.4 to 7.8-8.0, neuronal excitability increases greatly.

Example

• Hyperventilation (removal of CO₂) raises pH, potentially triggering epileptic seizures in predisposed individuals.

Effect of Acidosis (Decreased pH)

• If pH falls to 7.0, it causes Acidosis which depresses neuronal activity.

Example

• May lead to a coma in diabetic or uremic acidosis.

Effects of Hypoxia

• Neuronal excitability requires an adequate oxygen supply.
• If blood flow to the brain is interrupted for 3-7 seconds, consciousness is lost.

Effects of Drugs

• Stimulants like caffeine, theophylline, and theobromine increase neuronal excitability.
• Anesthetics increase the threshold for neuronal excitation through the mechanism of reducing synaptic transmission.

Signal Processing in Neuronal Pools

• The CNS is made of thousands to millions of neuronal pools.
• Each input fiber branches to synapse on many neurons.
• The area where an input fiber influences neurons is called the stimulatory field.

Concept of the Stimulatory Field

• Multiple inputs excite a neuron simultaneously which is called Spatial Summation.
• Repeated input from a single neuron over time causes excitation which is called Temporal Summation.

Neuronal Pool Organization

• Spatial and Temporal Summation determine the firing of a neuronal pool.
• Neurons receive enough input to generate action potentials and are located in the Discharge Zone (Excited Zone).
• Neurons receive subthreshold stimuli but are primed for excitation and are located in the Facilitated Zone (Subliminal Zone).
• Inhibitory inputs cause greater inhibition in the center and weaker inhibition at the periphery in Inhibitory Zones

Divergence and Convergence

• Divergence: Weak signals entering a neuronal pool excite many output neurons.
  • Amplifying divergence: One input excites many more output neuron
  • Divergence into multiple tracts: One signal is transmitted to different brain regions.
• Convergence: Multiple inputs excite a single neuron.
  • Single-source convergence (spatial summation)
  • Multiple-source convergence integrates information from different sources.

Reciprocal Inhibition

• A signal that excites one group of neurons simultaneously inhibits another group.

Example

• Limb movement: When flexor muscles are excited, inhibitory signals inhibit extensor muscles.

Reverberatory Circuits

• Signal continues even after the stimulus has stopped.
• Positive feedback within a neuronal circuit keeps the signal active.
• Involved in rhythmic activities like respiration and locomotion.

Types of Reverberatory Circuits

• Simple (one neuron reactivates itself) and more complex circuits involve excitatory and inhibitory neurons called Synaptic Afterdischarge.