Comprehensive Notes on Neurotransmission, Synapses, and Neural Circuitry

Defining the Synapse and Structural Classification

• Definition of Synapse: It is the point of contact between a neuron (either its axon or dendrite) and another neuron.

• Usage of the Term: "Synapse" can function as both a noun (e.g., "they form a synapse") and a verb (e.g., "they synapse").

• Structural Naming Convention: Synapses are named based on the specific structures of the presynaptic and postsynaptic neurons that come into contact. The name typically takes the structure of the presynaptic neuron first, followed by the structure of the postsynaptic neuron.

  • Exosomatic (Axosomatic): The axon of the presynaptic neuron contacts the body (soma) of the postsynaptic neuron.

  • Exo-exonic (Axoaxonic): The axon of the presynaptic neuron contacts the axon of the postsynaptic neuron.

  • Exodendritic (Axodendritic): The axon of the presynaptic neuron contacts the dendrite of the postsynaptic neuron.

  • Dendrodendritic: The dendrite of the presynaptic neuron contacts the dendrite of the postsynaptic neuron.

  • Dendrosomatic: The dendrite of the presynaptic neuron contacts the body (soma) of the postsynaptic neuron.

  • Somosomatic (Somatosomatic): The body of the presynaptic neuron contacts the body of the postsynaptic neuron. (Note: These are virtually never found in nature, though jokingly referred to as a "Valentine's Day" synapse where bodies touch bodies).

Frequency and Rarity of Synaptic Types

• Most Common Synapses: The most frequent types of contact in the nervous system are axodendritic and axosomatic.

• Less Common Synapses: Axoaxonic, dendrodendritic, and dendrosomatic synapses are found much less frequently within the nervous system.

• Unique Attributes: Somatosomatic synapses are non-existent in the human nervous system but serve as a theoretical/homework concept.

Functional Types of Synapses: Chemical vs. Electrical

• Chemical Synapses:

  • Mechanism: These utilize a synaptic cleft (a physical gap). When an action potential arrives, it cannot jump across the gap. Instead, the presynaptic neuron must release a chemical known as a neurotransmitter.

  • Directionality: Signals are unidirectional and follow a clear path (e.g., A to B, B to C).

  • Components: Requires an axon terminal, voltage-gated calcium channels, and synaptic vesicles.

  • Process: Action potential arrives $\rightarrow$ voltage-gated calcium channels open $\rightarrow$ calcium enters $\rightarrow$ vesicles fuse to the membrane and release neurotransmitters (e.g., Acetylcholine at the NMJ) $\rightarrow$ neurotransmitters diffuse across the cleft and bind to receptors on the postsynaptic cell.

  • Speed: These are slower than electrical synapses by milliseconds due to the time required for chemical diffusion and binding.

  • Predominance: These are the most common synapses despite being the slower type.

• Electrical Synapses:

  • Mechanism: Cells are physically connected (typically via gap junctions). There is no synaptic cleft.

  • Speed: They are significantly faster than chemical synapses because the action potential crosses directly to the next cell.

  • Directionality: These lack clear control and can be bidirectional (signal can go from neuron 3 to 4 or 4 to 3).

  • Location: Found in brain areas involving wake-up cycles, mental attention, emotional regulation, and memory.

Discovery of Chemical Signaling: Dr. Otto Loewi's Experiment

• The Problem: Historical skepticism existed regarding chemical signaling because it seemed too slow.

• The Experiment Setup:

  • Dr. Loewi removed a frog's heart, keeping the Vagus nerve (Cranial Nerve X) attached, and placed it in a beaker of solution.

  • The Vagus nerve is part of the parasympathetic nervous system (maintenance mode).

  • The heart's resting rate was $110\text{ beats per minute}$.

• The Stimulation: He stimulated the Vagus nerve, which slowed the heart rate down to $90\text{ beats per minute}$.

• The Proof: He took a sample of the "juice" (the solution) from the first beaker and poured it into a second beaker containing a separate frog heart (beating at $110\text{ bpm}$). Without direct nerve stimulation, the second heart also slowed to $90\text{ bpm}$.

• Conclusion: This proved that a chemical substance (later identified as Acetylcholine) had spilled into the solution and was responsible for carrying the signal to slow the heart.

Termination of Synaptic Signals

• Necessity: For every activation mechanism, there must be a mechanism to stop it.

• Primary Mechanisms of Termination:

  1. Endocytosis: The receptor, along with the bound neurotransmitter, may be brought back into the postsynaptic cell via endocytosis.

  2. Enzymatic Degradation: Specialized enzymes located in the synaptic cleft or astrocytes (neuroglia) break down the neurotransmitter into inactive components (e.g., Acetylcholine is broken down by Acetylcholinesterase).

  3. Reuptake: The neurotransmitter is taken back up into the presynaptic axonal terminal. This is economically efficient as the cell does not need to produce new neurotransmitters constantly.

Clinical Correlation: SSRIs and Depression

• Biological Hypothesis: Depression is sometimes attributed to insufficient levels of certain neurotransmitters, such as Serotonin, in the synaptic clefts of the brain.

• Mechanism of SSRIs (Selective Serotonin Reuptake Inhibitors):

  • Drugs like Prozac and Zoloft block the reuptake process.

  • By inhibiting the presynaptic neuron from reabsorbing serotonin, the concentration of serotonin remains higher in the synaptic cleft for a longer duration.

• Side Effects: Prolonged use (years) can sometimes lead to paradoxical effects like suicidal ideation, suggesting the biological basis of depression is more complex than simple neurotransmitter levels.

Nerve Damage and Regeneration

• Neuron Limitation: Mature neurons cannot divide. If a neuron dies, it is not replaced.

• Axonal Regrowth: While the neuron cannot divide, the axon can sometimes grow back if the cell body (soma) remains intact.

• Wallerian Degeneration: The portion of the axon distal to the site of injury naturally degenerates because it is severed from the support of the cell body.

• CNS vs. PNS Recovery:

  • PNS (Peripheral Nervous System): Axons have a better chance of reconnecting and recovering. Damage to a peripheral nerve (e.g., a cut finger) may be repaired by stitching nerves back together and using suction or leeches (blood suckers) to maintain circulation.

  • CNS (Central Nervous System): Axons in the brain and spinal cord are bundled into tracts (not nerves). If a tract in the CNS is damaged, regrowth is extremely unlikely, making CNS damage more permanent than PNS damage.

• Physical Therapy (PT) Metaphor: A PT moves a paralyzed limb to "remind" the brain and surrounding neurons that the muscle still exists, encouraging growing nerve endings to move toward the target (mimicking curiosity in an abandoned house that suddenly plays music).

Postsynaptic Potentials (PSPs)

• Resting Membrane Potential (RMP): Commonly $-70\,mV$.

• Threshold: $-55\,mV$. Crossing this threshold triggers an action potential via voltage-gated sodium channels.

• Excitatory Postsynaptic Potential (EPSP):

  • The membrane potential becomes more positive (e.g., $-70\,mV \rightarrow -60\,mV$).

  • This is called depolarization.

  • It increases the likelihood of reaching the $-55\,mV$ threshold.

• Inhibitory Postsynaptic Potential (IPSP):

  • The membrane potential becomes more negative (e.g., $-70\,mV \rightarrow -80\,mV$).

  • This is called hyperpolarization.

  • It decreases the likelihood of an action potential by moving the potential further from the threshold.

• Ionic Basis Summary:

  • Open Sodium ($Na^+$) Channel: $Na^+$ enters, causing EPSP.

  • Open Calcium ($Ca^{2+}+$) Channel: $Ca^{2+}$ enters, causing EPSP.

  • Open Potassium ($K^+$) Channel: $K^+$ leaves, causing IPSP.

  • Open Chloride ($Cl^-$) Channel: $Cl^-$ enters, causing IPSP (since $Cl^-$ is negative).

Synaptic Summation

• Temporal Summation: A single presynaptic neuron sends multiple signals in rapid succession to reach the threshold on the postsynaptic cell.

• Spatial Summation: Multiple different presynaptic neurons fire simultaneously, adding their collective strength to reach the threshold.

• Neural Logic Example: A single motor neuron (to punch someone) receives input from:

  • Humanity Neuron: Sending IPSPs (don't punch).

  • Indicator Neuron: Sending IPSPs (don't punch).

  • Legal Neuron: Sending IPSPs (fear of being sued).

  • Logic Neuron: Sending IPSPs (fear of the target's big brothers).

  • Punk Neuron: Sending EPSPs (a free country, just do it).

  • Outcome: The neuron "sums" these signals. If IPSPs outweigh EPSPs, no action potential occurs, and no punch is thrown.

• Averaging: A single neuron can receive up to $10,000$ synaptic contacts.

Chemical Classification of Neurotransmitters

• Group 1: Acetylcholine (ACh):

  • The first identified neurotransmitter.

  • Classified as a "classical" neurotransmitter.

  • Released at the NMJ, in the brain, and in the autonomic nervous system.

  • Effect is location-dependent: Excitatory in skeletal muscle (moves joints); Inhibitory in cardiac muscle (slows heart rate).

• Group 2: Biogenic Amines:

  • Most abundant group in the nervous system.

  • Catecholamines: Include Dopamine, Norepinephrine, and Epinephrine. Involved in human behavior and the sympathetic nervous system.

  • Indolamines: Include Serotonin (biological clock, behavior) and Histamine.

  • Synthesis Pathway: Tyrosine $\rightarrow$ L-Dopa $\rightarrow$ Dopamine $\rightarrow$ Norepinephrine $\rightarrow$ Epinephrine. (Specific enzymes like Tyrosine hydroxylase are required).

• Group 3: Amino Acids:

  • Found predominantly in the CNS.

  • Includes GABA (Gamma-aminobutyric acid), Glycine, Aspartate, and Glutamate.

  • GABA: The most famous inhibitory neurotransmitter. Gabapentin is a synthetic mimic used to stop seizures.

  • Glutamate: The most abundant amino acid neurotransmitter.

• Group 4: Peptides (Small Proteins):

  • Substance P: Involved in pain signaling.

  • Endorphins/Enkephalins: Natural opioids that act like morphine to block pain and cause hallucination/euphoria (e.g., a mother lifting a burning car during a crisis without feeling pain).

  • Gut-Brain Peptides: Found in the digestive system (which has more neurons than the spinal cord). Includes Somatostatin and Cholecystokinin.

• Group 5: Purines and Noble Gases:

  • Purines: ATP, known as energy, can act as a neurotransmitter associated with pain.

  • Nitric Oxide (NO): A potent vasodilator (widens blood vessels). Used in memory and learning. Nitroglycerin tablets for heart attacks are converted into NO to increase blood flow.

  • Carbon Monoxide (CO): A known poison that also functions as a signaling neurotransmitter (mechanism largely unknown).

Neural Circuitry and Processing

• Diversion (Divergent Circuit): One neuron stimulates multiple neurons. Typically used for amplification (one signal becomes many).

• Conversion (Convergent Circuit): Multiple neurons stimulate one single focal neuron. Used for focus/attention where the brain filters multiple inputs into one representative response.

• Reverberating Circuit: Signal travels in a chain, but later neurons loop back to stimulate earlier ones. Creates a rhythmic, continuing signal. Involved in rhythmic activities like breathing.

• Parallel Discharge Circuit: A single neuron contacts multiple parallel rows of neurons that all eventually converge on one output cell. Used for signal enhancement.

• Serial Processing: A simple step-by-step pathway (e.g., Reflexes—stimulus $\rightarrow$ sensory neuron $\rightarrow$ interneuron $\rightarrow$ motor neuron). This happens before the brain even consciously processes the event.

• Parallel Processing: Processing multiple modalities simultaneously.

  • Example: Smelling a muffin triggers not just the identification of food, but memory of a grandmother, or a memory of a first date sharing a muffin. One stimulus activates multiple different pathways at once.