Synaptic Transmission – Comprehensive Study Notes

Membrane Architecture & Selective Permeability

• Neuronal membrane
– Uniform bi-lipid layer ≈ 8\,\text{nm} thick (≈ 1/10{,}000^{\text{th}} width of a human hair).
– Embedded proteins: ion channels, pumps, receptors.
• Selective permeability
– Molecules that diffuse freely through always-open pores: \text{O}2,\;\text{CO}2,\;\text{H}_2\text{O},\;\text{urea}.
– Biologically critical ions (Na$^+$, K$^+$, Ca$^{2+}$, Cl$^-$) cross only through gated channels that cycle between open/closed states.

Resting Membrane Potential (RMP)

• Definition: Stable voltage difference between cytoplasm & extracellular fluid at rest.
– Typical value: V_{\text{rest}} \approx -70\,\text{mV}.
– Measured with microelectrodes relative to extracellular space.
• Functional importance
– Stores electrochemical energy → basis for rapid signaling.
• If all channels were open → ions would flow down gradients → depolarization → loss of RMP.

Ionic Basis of RMP

• Unequal ion distributions
– High extracellular: [\text{Na}^+], [\text{Cl}^-].
– High intracellular: [\text{K}^+], [\text{A}^-] (negatively charged proteins).
• Driving forces
– Diffusion pressure: ions move down concentration gradients.
– Electrostatic pressure: opposite charges attract, like charges repel.
• Key players
– Leak channels (mainly K$^+$).
– Sodium-potassium pump (Na$^+$/K$^+$-ATPase):
• Active transport, requires ATP.
• Exchanges 3\,\text{Na}^+{\text{out}} \leftarrow 2\,\text{K}^+{\text{in}} per cycle.
• Maintains [\text{Na}^+]{\text{out}} > 10\times [\text{Na}^+]{\text{in}} & [\text{K}^+]{\text{in}} \gg [\text{K}^+]{\text{out}}.
• Pump activity is triggered/enhanced by repetitive action potentials.

Graded (Postsynaptic) Potentials

• Generated by ligand-gated channels in dendrites/soma.
• Two flavors
– Excitatory postsynaptic potentials (EPSPs): depolarize; bring Vm toward threshold. – Inhibitory postsynaptic potentials (IPSPs): hyperpolarize; drive Vm away from threshold.
• Properties
– Graded amplitude (proportional to stimulus strength).
– Decremental: decay with distance.
– Rapid; no refractory period.

Summation Mechanisms

• Spatial summation
– Simultaneous inputs from different locations combine at axon hillock.
– Example outcomes (from diagrams):
• Two EPSPs \Rightarrow larger EPSP.
• Two IPSPs \Rightarrow larger IPSP.
• EPSP + IPSP \Rightarrow cancelation.
• Temporal summation
– Rapid succession from the same synapse; potentials add if inter-pulse interval < membrane time constant.
• Influence of synapse location
– Inputs closer to axon trigger zone experience less decay → exert larger impact.

Action Potential (AP) — Generation & Phases

• Threshold
– Typical: V_{\text{th}} \approx -55\,\text{mV}.
– Subthreshold stimulus → small, decaying response.
– Supra-threshold (no matter how large) → stereotyped AP.
• All-or-None Law
– Within one neuron, APs are uniform in amplitude (≈ \text{peak 30–40 mV above 0}) and velocity.
• Sequence (detailed):

1. Resting state: Na$^+$ outside, K$^+$ inside.

2. Reaching threshold opens fast voltage-gated Na$^+$ channels → Na$^+$ influx → rapid depolarization.

3. Just after peak (≈ +35 to +40\,\text{mV}) Na$^+$ channels inactivate (close).

4. Voltage-gated K$^+$ channels, which opened slowly, now dominate → K$^+$ efflux → repolarization.

5. Continued K$^+$ efflux overshoots RMP → hyperpolarization.

6. K$^+$ channels close; membrane returns to RMP with help of pump.
   – Graph convention labels: Rising phase (1–2), Peak (3), Repolarization (4), Hyperpolarization (5).

Refractory Periods

• Absolute refractory (≈ first 1–2 ms)
– Na$^+$ channels inactivated; new AP impossible regardless of stimulus.
• Relative refractory (follows absolute)
– Some Na$^+$ channels reset, K$^+$ still open; higher-than-normal stimulus can elicit AP.

Axonal Conduction

• Unmyelinated axon
– Propagation is active, non-decremental, but slower.
– Na$^+$ influx at one segment depolarizes next = wave of APs.
– Two directions possible; physiologically orthodromic (soma → terminal) dominates.
• Myelinated axon
– Myelin sheath + Nodes of Ranvier → saltatory conduction.
– Benefits: velocity ↑, energy cost ↓ (Na$^+$/K$^+$ exchange limited to nodes).
– Velocity proportional to axon diameter; large myelinated fibers fastest.
• Axonless/short-axon neurons
– Conduct electrotonically; decremental spread.

Synaptic Anatomy & Diversity

• Core elements: presynaptic bouton, synaptic cleft, postsynaptic density.
• Dendritic spines: plastic protrusions receiving most excitatory inputs.
• Directional categories
– Axodendritic (classic), axosomatic, axo-axonic (presynaptic inhibition), dendro-dendritic, dendro-axonic.
• Directed vs. nondirected synapses
– Nondirected: transmitter released from varicosities → diffuses to targets (volume transmission).
• Gap junctions (electrical synapses)
– Connexon pores allow bidirectional ionic flow; near-instaneous; common in inhibitory interneuron networks & glia-neuronal coupling.

Neurotransmitter Release Cycle

• Trigger: AP invades terminal → voltage-gated Ca$^{2+}$ channels open.
• Steps

1. Ca$^{2+}$ influx.

2. Ca$^{2+}$–synaptotagmin complex initiates vesicle fusion (exocytosis).

3. Transmitter expelled into \sim 20–40\,\text{nm} cleft.

4. Possibility of co-release (classic NT + neuropeptide).
   • Nondirected release visualized along axon branches.

Neurotransmitter Clearance

• Two principal deactivation mechanisms
– Reuptake via transporters (e.g., DAT, SERT, NET).
– Enzymatic degradation (e.g., AChE for acetylcholine, MAO for monoamines).
• Vesicle & membrane components recycled via endocytosis.

Classical Neurotransmitter Families (Quick Mnemonics)

• Adrenaline (epinephrine) – “fight-or-flight.”
• Noradrenaline (norepinephrine) – vigilance/concentration.
• Dopamine – reward & motor control.
• Serotonin – mood, appetite, sleep.
• GABA – primary inhibitory ("calming").
• Glutamate – primary excitatory; learning/memory.
• Acetylcholine – learning & neuromuscular junction.
• Endorphins – endogenous opioids; euphoria & analgesia.

Drug Modulation of Synaptic Transmission

• Agonists: enhance transmitter effect via—
– ↑ synthesis (supply more precursor).
– ↓ degradative enzymes.
– ↑ vesicular release.
– Block presynaptic autoreceptors (disinhibit release).
– Post-synaptic receptor activation or sensitivity increase.
– Block reuptake/degradation (e.g., SSRIs, MAOIs).
• Antagonists: diminish transmitter effect via—
– Inhibit synthesis (destroy enzymes).
– Promote vesicle leakage & enzymatic destruction.
– Block release (e.g., botulinum toxin on ACh).
– Activate autoreceptors (inhibit release).
– Post-synaptic receptor blockade (e.g., antipsychotics on D2).

Landmark Discoveries in Behavioral Pharmacology

• Receptor subtypes (e.g., \alpha,\;\beta adrenergic; \text{D}1–\text{D}5 dopamine).
• Endogenous opioids (endorphins, enkephalins) → clarified analgesia & addiction.
• Antischizophrenic (antipsychotic) drugs → dopaminergic hypotheses.

Autonomic & Somatic Organization Review

• Peripheral Nervous System (PNS)
– Somatic: sensory & motor to skeletal muscle.
– Autonomic: sympathetic (fight/flight) vs. parasympathetic (rest/digest).
– Preganglionic vs. postganglionic fiber map (cranial, thoracic, lumbar, sacral levels; vagus nerve dominance in parasympathetic).
• Central Nervous System (CNS): brain & spinal cord.

Brain Region Context (for synaptic integration examples)

• Frontal lobe: planning, emotion, motor (precentral gyrus = primary motor cortex).
• Parietal lobe: somatosensory (postcentral gyrus).
• Temporal lobe: hearing, advanced visual.
• Occipital lobe: vision.
• Prefrontal cortex: executive; integrates long-range synaptic inputs.

Practical / Ethical / Real-World Notes

• Ion channelopathies → epilepsy, migraine (importance of AP fidelity).
• Myelin disorders (e.g., MS) highlight saltatory conduction energetics.
• Pharmacological agents (SSRIs, antipsychotics, opioids) need nuanced agonist/antagonist understanding to minimize side-effects & abuse.
• Gap junction physiology underpins emerging neuro-glial therapeutic strategies.

Multimedia & Further Study Resources

• AP in mouse visual cortex (YouTube IDs: WOgwrCIXX40, Cw5PKV9Rj30).
• Resting potential & pump animations: ZKE8qK9UCrU, _bPFKDdWlCg.
• Exocytosis demo: 90cj4NX87Yk.
• Crash-Course Neuroscience app + flashcards.
• HyperPhysics interactive AP tutorial: http://hyperphysics.phy-astr.gsu.edu/hbase/Biology/actpot.html

Quick Formulae & Numerical Anchors

• RMP ≈ -70\,\text{mV}; Threshold ≈ -55\,\text{mV}; AP peak ≈ +40\,\text{mV} (can vary up to +130\,\text{mV} in diagrams).
• Na$^+$/K$^+$ pump cycle: 3\,\text{Na}^+{\text{out}}/2\,\text{K}^+{\text{in}}, 1 ATP.
• Time scale of AP: ~1–2\,\text{ms} rising, total < 5\,\text{ms}.
• Membrane thickness: 8\,\text{nm}.

End-of-Lecture Reminder

• Review videos & flashcards.
• Appreciate synaptic complexity → ground for pharmacological innovation & neurological pathology understanding.