Synaptic Transmission

Fundamentals of Synaptic Transmission

• Synaptic transmission is defined as the major process through which electrical signals are transferred between neurons and muscle cells or between neurons and sensory receptors.

• It occurs within the nervous system as a point-to-point interaction between two neurons at specialized junctions called synapses.

• The presynaptic cell is the neuron sending the signal, typically originating from the axon hillock (responsible for action potential generation) and traveling through the myelin sheath to the synaptic terminals.

• The postsynaptic cell is the receiving cell, which contains receptors (e.g., where Acetylcholine/ACh is released).

• The signal direction is unidirectional in chemical synapses, moving from the presynaptic cell to the postsynaptic cell.

Classification and Properties of Synapses

Synapses are categorized into two major groups: electrical and chemical.

1. Electrical Synapses

• Structure: Composed of numerous gap-junction channels that allow ions to flow directly from the cytoplasm of one cell to another.

• Communication: There is direct communication between the cytoplasm of the two cells, facilitating very quick transport.

• Component Units: Each gap junction is formed by connexons. Each connexon is made up of $6$ identical subunits called connexins.

• Main Properties:   - Speed: They are exceptionally fast with essentially no synaptic delay.   - Directionality: Transmission is bidirectional; current generated in either cell can flow across the gap junction to influence the neighboring cell.

• Physiological Relevance: They are involved in functions requiring rapid coordination, such as certain cardiac responses (e.g., experiments showing the slowing of heart rate via chemical transfer of liquid).

2. Chemical Synapses

• Structure: These consist of a terminal bouton of an axon (presynaptic), a synaptic cleft (diffusion space), and a postsynaptic cell.

• Mechanism: Communication occurs via chemical intermediaries known as neurotransmitters.

• Synaptic Cleft: This is also known as the synaptic gap. Unlike electrical synapses, there is no direct communication between the cytoplasm of the two cells.

• Functional Anatomy:   - Synaptic Vesicles: Small, membrane-enclosed structures packed with neurotransmitters. Shape and size vary by transmitter type.   - Active Zones: Regions on the presynaptic membrane containing electron-dense material and proteins specifically involved in neurotransmitter release.   - Mitochondria: Located in the terminal to provide ATP for the energy-intensive process of transmission.   - Postsynaptic Receptors: Specific proteins that bind neurotransmitters to trigger either excitation or inhibition.

Criteria and Classification of Neurotransmitters

Criteria for Identification

To be classified as a neurotransmitter, a molecule must meet established criteria:

• The substance must be synthesized in or present in the presynaptic terminal.

• When released, the chemical must produce a measurable response in the target cell.

• Specific receptors for the substance must exist on the postsynaptic membrane.

• There must be a specific mechanism for its removal from the synaptic site.

• Experimental application of the chemical to the target cell must produce the same response as natural release.

Classification of Synaptic Transmitters

Class I: Small-Molecule, Rapidly Acting Transmitters

• Class I: Acetylcholine ($ACh$).

• Class II (The Amines): Norepinephrine, Epinephrine, Dopamine, Serotonin, Histamine.

• Class III (Amino Acids): Gamma-aminobutyric acid ($GABA$), Glycine, Glutamate, Aspartate.

• Class IV: Nitric oxide ($NO$).

Neuropeptides, Slowly Acting Transmitters, or Growth Factors

• Hypothalamic-Releasing Hormones: Thyrotropin-releasing hormone, Luteinizing hormone–releasing hormone, Somatostatin (growth hormone inhibitory factor).

• Pituitary Peptides: Adrenocorticotropic hormone ($ACTH$), $\beta$-Endorphin, $\alpha$-Melanocyte-stimulating hormone, Prolactin, Luteinizing hormone, Thyrotropin, Growth hormone, Vasopressin, Oxytocin.

• Peptides Acting on Gut and Brain: Leucine enkephalin, Methionine enkephalin, Substance P, Gastrin, Cholecystokinin, Vasoactive intestinal polypeptide ($VIP$), Nerve growth factor, Brain-derived neurotropic factor, Neurotensin, Insulin, Glucagon.

• From Other Tissues: Angiotensin II, Bradykinin, Carnosine, Sleep peptides, Calcitonin.

Mechanism of Chemical Neurotransmission

The Role of Calcium ($Ca^{2+}$)

• Depolarization: The arrival of an action potential at the presynaptic membrane causes depolarization.

• Channel Activation: This depolarization triggers the opening of voltage-gated $Ca^{2+}$ channels.

• Concentration Gradient: Extracellular $[Ca^{2+}]$ is high relative to intracellular $[Ca^{2+}]$. This electrochemical gradient favors the entry of $Ca^{2+}$ into the presynaptic terminal.

• The Signal: Calcium entry is the primary signal for neurotransmitter release.

Exocytosis and Release

• Vesicle Fusion: Synaptic vesicles containing neurotransmitters fuse with the presynaptic membrane specifically at the active zones.

• Sensor Proteins: Calcium binds to sensor proteins such as synaptotagmin, which stimulates the fusion of the vesicle membrane with the plasma membrane.

• Exocytosis: The neurotransmitter is released into the synaptic cleft through exocytosis.

• Diffusion: The neurotransmitter molecules diffuse rapidly across the synaptic cleft to reach the postsynaptic receptors.

Postsynaptic Receptors and Potential Changes

There are two major classes of transmitter receptors that determine the speed and nature of the postsynaptic response.

1. Ionotropic Receptors (Ligand-Gated Ion Channels)

• Mechanism: Direct gating. Binding of the neurotransmitter ligand triggers the immediate opening of the ion channel pore.

• Characteristics: Mediate "fast" synaptic transmission.

• Pentameric Superfamily: Includes $ACh$, $GABA_A$, and Glycine receptors.   - These consist of $5$ subunits arranged around a central channel.   - Each subunit contains three domains: Extracellular (ligand-binding), Transmembrane, and Intracellular.

• Nicotinic Acetylcholine Receptor (nAChR):   - Found in central and peripheral nervous systems.   - Selective to cations; permeable to $Na^+$ and $K^+$ (and some $Ca^{2+}$ isoforms).   - Binding of $2$ $ACh$ molecules causes a conformational change opening the channel.   - Results in excitatory postsynaptic potential ($EPSP$) due to $Na^+$ influx exceeding $K^+$ efflux.

• Type-A $\gamma$-aminobutyric acid receptors ($GABA_ARs$):   - Mediate rapid inhibitory synaptic transmission in the brain.   - $GABA$ binding opens $Cl^-$ ion channels.   - $Cl^-$ entry causes hyperpolarization and an inhibitory postsynaptic potential ($IPSP$).

2. Metabotropic Receptors (G Protein-Coupled Receptors)

• Mechanism: Indirect gating. The receptor is not a channel but is coupled to a G-protein.

• G-Protein Structure: Composed of $\alpha$, $\beta$, and $\gamma$ subunits aggregated together when inactive.

• Activation Process:   - Ligand binds to the receptor.   - The $\alpha$ subunit dissociates from the $\beta$-$\gamma$ complex.   - Either the $\alpha$ or the $\beta$-$\gamma$ complex moves through the membrane to bind to an effector protein (enzyme or ion channel).

• Characteristics: Mediate "slow" synaptic transmission.

• Muscarinic Acetylcholine Receptors (mAChRs):   - Binding of $ACh$ causes the $\beta$-$\gamma$ complex to dissociate and bind to a $K^+$ channel.   - This causes $K^+$ efflux (outward diffusion), resulting in hyperpolarization ($IPSP$) and a slowing of the heart rate.

Excitatory and Inhibitory Potentials (EPSP and IPSP)

Excitatory Postsynaptic Potential ($EPSP$)

• Ion Flow: Opening of channels allowing more $Na^+$ or $Ca^{2+}$ to enter the cell than $K^+$ to exit.

• Effect: Graded depolarization; the inside of the membrane becomes less negative.

• Outcome: Moves the membrane potential closer to the threshold. If threshold is reached, an action potential is generated.

Inhibitory Postsynaptic Potential ($IPSP$)

• Ion Flow: Opening of $K^+$ gates (efflux) or $Cl^-$ gates (influx).

• Effect: Graded hyperpolarization; the inside of the membrane becomes more negative.

• Outcome: Moves the membrane potential farther from the threshold, making it more difficult to generate an action potential.

Synaptic Integration and Summation

Individual inputs are usually too small to reach the spiking threshold; therefore, neurons must integrate thousands of inputs.

• Spatial Summation: The addition of postsynaptic potentials generated simultaneously at many different synapses on the same neuron.

• Temporal Summation: The addition of postsynaptic potentials generated at a single synapse when impulses are received in rapid succession (within a short period).

Termination of Neurotransmitter Action

Timely removal of the transmitter is critical to prevent overstimulation and ensure the next signal can be received.

1. Reuptake: Transmitters are taken back into the presynaptic terminal or glial cells (e.g., Glutamate).

2. Enzymatic Degradation: Enzymes break down the transmitter in the cleft (e.g., Acetylcholinesterase).

3. Diffusion: The transmitter simply diffuses away from the synaptic cleft.

Specific Examples of Termination

• Acetylcholine ($ACh$): Broken down by acetylcholinesterase ($AChE$) into choline and acetate. Choline is transported back into the axon terminal via a choline transporter to be reused for synthesis with Acetyl CoA.

• Glutamate: This is the main excitatory neurotransmitter in the CNS. At high concentrations, it is a potent neurotoxin. Its activity is strictly limited by membrane transporter proteins that move it into presynaptic terminals and glial cells to prevent cell death.

Comparison: Graded Potentials vs. Action Potentials