Describe synaptic transmission and neurotransmitters

The Mechanism: From Electrical to Chemical and Back

Step-by-Step Derivation from First Principles

WHAT happens at a synapse? An action potential arriving at the axon terminal triggers neurotransmitter release, which then binds to receptors and generates a response in the postsynaptic cell.

WHY this elaborate process? Direct electrical synapses (gap junctions) exist but are rare in vertebrates because chemical synapses offer:

1. Amplification: One vesicle releases thousands of molecules, each can open ion channels
2. Plasticity: Synapse strength can change (basis of learning and memory)
3. Unidirectional flow: Information flows one way, creating organized circuits
4. Integration: Postsynaptic cell can sum hundreds of synaptic inputs

Phase 1: Action Potential Arrival

When an action potential reaches the axon terminal:

WHY does voltage matter? The presynaptic membrane contains voltage-gated Ca²⁺ channels. At resting potential (-70 mV), these are closed. When depolarization reaches the terminal (approaching +40 mV at the peak of action potential):

$P_{open} = \frac{1}{1 + e^{-(V-_{half})/k}}$

Where $V_{half}$ ≈ -20 mV for Ca²⁺ channels, $k$ is the voltage sensitivity (~5 mV).

The critical insight: Ca²⁺ channels open when voltage exceeds threshold. External [Ca²⁺] ≈ 2 mM, internal ≈ 0.001 mM → huge concentration gradient.

$E_{Ca} = \frac{RT}{zF} \ln\frac{[Ca^{2+}]_{out}}{[Ca^{2+}]_{in}}$

At 37°C (310 K):

• $R = 8.314$ J/(mol·K)
• $F = 96,485$ C/mol
• $z = +2$ (Ca²⁺ charge)

$E_{Ca} = \frac{8.314 \times 310}{2 \times 96,485} \ln\frac{2000}{0.1} = 0.0133 \times \ln(20,000) = 0.0133 \times 9.9 \approx +132 \text{ mV}$

WHY this step? This enormous driving force (+132 mV equilibrium potential vs. -70 mV resting) means Ca²⁺ rushes in when channels open. This is intentional—Ca²⁺ acts as the trigger.

Phase 2: Vesicle Fusion (Exocytosis)

HOW does Ca²⁺ cause release?

Incoming Ca²⁺ binds to synaptotagmin proteins on synaptic vesicles. This is a cooperative process:

$P_{release} \propto [Ca^{2+}]^4_{local}$

WHY fourth power? Multiple Ca²⁺ ions (typically 4-5) must bind to create a conformational change. This creates a steep, switch-like response—small Ca²⁺ increase = no release; sufficient Ca²⁺ = massive release.

The vesicle has SNARE proteins (synaptobrevin, syntaxin, SNAP-25) that zipper together, pulling vesicle membrane to presynaptic membrane:

1. Ca²⁺-synaptotagmin removes the "brake" on SNARE complex
2. SNAREs pull membranes together (releasing ~65 kJ/mol of energy)
3. Lipid bilayers fuse, creating a fusion pore
4. Neurotransmitters diffuse out into cleft

Time scale: From Ca²⁺ entry to release = 0.2-0.5 ms (incredibly fast!).

Given: Release probability $P \propto [Ca^{2+}]^4$

Calculate the fold-increase in release probability:

$\frac{P_{stimulated}}{P_{resting}} = \frac{(10)^4}{(0.1)^4} = \frac{10,000}{0.0001} = 10^8$

WHY this step? The fourth-power relationship means a 100-fold Ca²⁺ increase → 100million-fold increase in release probability. This ensures neurotransmitter release ONLY happens during action potentials, not from random baseline Ca²⁺ fluctuations. It's a noise filter.

Phase 3: Diffusion Across Synaptic Cleft

Neurotransmitters diffuse across the 20-40 nm cleft in ~0.1-0.3 ms.

From Fick's Law: $J = -D \frac{dC}{dx}$

For acetylcholine, $D ≈ 3.3 \times 10^{-10}$ m²/s. Time to diffuse distance $d$:

$t = \frac{d^2}{2D} = \frac{(30 \times 10^{-9})^2}{2 \times 3.3 \times 10^{-10}} = \frac{9 \times 10^{-16}}{6.6 \times 10^{-10}} ≈ 1.4 \times 10^{-6} \text{ s} = 1.4 \text{ μs}$

WHY so fast? The cleft is incredibly narrow—distance scales quadratically in diffusion time, so keeping it tiny ensures rapid transmission.

Phase 4: Receptor Binding

Neurotransmitters bind to receptors on the postsynaptic membrane. Two main types:

A) Ionotropic receptors (ligand-gated ion channels):

• Direct: neurotransmitter binding opens the channel
• Fast: 1-2 ms response time
• Example: nicotinic acetylcholine receptor (opens Na⁺/K⁺ channel)

B) Metabotropic receptors (G-protein coupled):

• Indirect: neurotransmitter activates G-protein → second messenger cascade
• Slow: 50-100+ ms response time
• Example: muscarinic acetylcholine receptor (activates G-proteins)

WHY two types? Ionotropic = fast reflexes, immediate responses. Metabotropic = modulatory, long-lasting changes, involved in mood and learning.

$I_{ion} = g_{max} \cdot P_{open} \cdot (V_m - E_{ion})$

Where:

• $g_{max}$ = maximum conductance when all channels open
• $P_{open}$ = fraction of receptors bound and open
• $V_m$ = membrane potential
• $E_{ion}$ = reversal potential for that ion

For excitatory postsynaptic potential (EPSP): Na⁺ channels open, $E_{Na}$ ≈ +60 mV For inhibitory postsynaptic potential (IPSP): Cl⁻ channels open, $E_{Cl}$ ≈ -70 mV

WHY this matters: The postsynaptic cell integrates hundreds of EPSPs and IPSPs. If the sum reaches threshold at the axon hillock, a new action potential fires.

Given:

• Single channel conductance: 20 pS (picosiemens) = $20 \times 10^{-12}$ S
• Resting $V_m = -70$ mV
• Receptors are non-selective cation channels with reversal $E_{rev} = 0$ mV

Calculate the total current:

$I = n \cdot g_{single} \cdot (V_m - E_{rev}) = 1000 \times 20 \times 10^{-12} \times (-70 \times 10^{-3} - 0)$ $I = 20 \times 10^{-9} \times (-0.07) = -1.4 \times 10^{-9} \text{ A} = -1.4 \text{ nA}$

Negative current means positive charge entering (by convention).

Calculate the voltage change using membrane capacitance ($C_m ≈ 1$ μF/cm², typical neuron area 0.01 cm²):

$\Delta V = \frac{Q}{C} = \frac{I \cdot \Delta t}{C_m}$

For a 5 ms EPSP duration: $\Delta V = \frac{1.4 \times 10^{-9} \times 5 \times 10^{-3}}{10^{-8}} = \frac{7 \times 10^{-12}}{10^{-8}} = 0.7 \text{ mV}$

WHY this step? This shows a single synapse produces a tiny voltage change (~0.7 mV). The neuron needs input from many synapses simultaneously to reach the ~15-20 mV depolarization needed to fire. This is spatial and temporal summation.

Phase 5: Termination

Neurotransmitter signaling must stop, or the synapse would fire continuously. Three mechanisms:

1. Reuptake: Transporter proteins on presynaptic membrane pump neurotransmitter back inside

• Example: Serotonin transporter (SERT), Dopamine transporter (DAT)
• WHY? Recycling saves energy—resynthesis is metabolically expensive

2. Enzymatic degradation: Enzymes in the cleft break down neurotransmitters

• Example: Acetylcholinesterase breaks ACh → acetate + choline (in <1 ms!)
• WHY? Permanently removes the signal for rapid reset

3. Diffusion away: Some neurotransmitters simply drift out of the cleft

• WHY? Backup mechanism for spillover and volume transmission

Given:

• $k_{cat}$ (turnover number) ≈ 25,000 s⁻¹
• Each molecule of enzyme breaks 25,000 ACh molecules per second

If a synapse releases 10,000 ACh molecules and there are 1000 AChE molecules in the cleft:

Calculate clearance time:

$t = \frac{\text{molecules of ACh}}{\text{molecules of AChE} \times k_{cat}} = \frac{10,000}{1000 \times 25,000} = \frac{10,000}{25,000,000} = 4 \times 10^{-4} \text{ s} = 0.4 \text{ ms}$

WHY this step? This shows ACh is cleared almost as fast as it's released. This allows the neuromuscular junction to fire at high frequencies (100+ Hz) without signals "bluring together."

Major Neurotransmitters

HOW are they synthesized?

• Acetylcholine: Acetyl-CoA + Choline → ACh (via choline acetyltransferase)
• Glutamate: From α-ketoglutarate (Krebs cycle intermediate) via transamination
• GABA: From glutamate via glutamic acid decarboxylase (GAD) + vitamin B6
• Catecholamines: Tyrosine → L-DOPA → Dopamine → Norepinephrine → Epinephrine (sequential hydroxylations)

WHY it feels right: Linear thinking—more input = more output.

The REALITY: Receptors saturate. If you already occupy 90% of receptors, doubling neurotransmitter might only increase occupancy to 95%, a tiny change in response.

From receptor binding kinetics: $\theta = \frac{[NT]}{[NT] + K_d}$

Where $\theta$ = fraction of receptors bound, $K_d$ = dissociation constant.

Example: If $K_d = 1$ μM and [NT] = 10 μM: $\theta = \frac{10}{10+1} = 0.91$

Double neurotransmitter to 20μM: $\theta = \frac{20}{20+1} = 0.95$

Only increased from 91% to 95% occupancy—not a doubling!

The FIX: Synaptic strength is tuned by:

1. Number of receptors on postsynaptic membrane (upregulation/downregulation)
2. Number of vesicles released (presynaptic plasticity)
3. Receptor sensitivity (phosphorylation state, subunit composition)

This is why drugs and learning change synapse strength through these mechanisms, not just by flooding more neurotransmitter.

• Glutamate = excitatory (depolarizes, makes firing MORE likely)
• GABA = inhibitory (hyperpolarizes or clamps, makes firing LESS likely)

For receptor speed: "Ionotropic Is Instant, Metabotropic is Measured"

• Ionotropic = ion channel = fast (1-2 ms)
• Metabotropic = G-protein = slower (50-100 ms)

Synaptic Plasticity: The Basis of Learning

WHY does this matter beyond just transmission?

Synapses are not fixed relays—they strengthen or weaken based on activity:

Long-Term Potentiation (LTP): High-frequency stimulation → stronger synapse

• Mechanism: More AMPA receptors inserted into postsynaptic membrane
• WHY? "Neurons that fire together, wire together" (Hebian learning)

Long-Term Depression (LTD): Low-frequency stimulation → weaker synapse

• Mechanism: AMPA receptors removed from membrane
• WHY? Prunes unused connections, prevents runaway excitation

The critical insight: Your memories, skills, and personality are encoded in the pattern of synaptic strengths across billions of synapses. Learning doesn't create new neurons (mostly)—it rewires synapses.

The receiving house has special mailboxes (receptors) that catch these bubles. When enough bubbles arrive and get caught, the receiving house gets excited and might decide to send its own messages to other houses.

The cool part? If two houses talk to each other a lot, they build more mailboxes and get better at communicating—that's how you learn and remember things! And different types of bubles do different things: some make the next house more likely to send messages (excitatory), and some calm it down (inhibitory). This way, your brain can control which messages spread and which don't, making it possible to think, move, and feel.

Connections

• Action Potential Propagation — the electrical signal that triggers synaptic transmission
• Neuron Structure — anatomy of presynaptic terminal and axon
• Membrane Potential — basis for understanding driving forces and equilibrium potentials
• Signal Integration — how postsynaptic neurons sum EPSPs and IPSPs
• Neuromuscular Junction — specialized synapse between motor neuron and muscle
• Neurodegenerative Diseases — many (Alzheimer's, Parkinson's) involve synaptic dysfunction
• Drug Mechanisms — most psychoactive drugs target neurotransmitter systems
• Learning and Memory — synaptic plasticity (LTP/LTD) as the cellular basis

#flashcards/biology

What is a synapse? :: The functional junction between two neurons (or neuron and effector), consisting of presynaptic terminal, synaptic cleft (20-40 nm gap), and postsynaptic membrane, where electrical signals are converted to chemical signals via neurotransmitters.

What are EPSPs and IPSPs? :: Excitatory PostSynaptic Potentials (EPSPs) are depolarizations caused by openingation channels (e.g., Na⁺), making firing more likely. Inhibitory PostSynaptic Potentials (IPSPs) are hyperpolarizations or clamp caused by opening Cl⁻ or K⁺ channels, making firing less likely.

Name the three mechanisms for terminating neurotransmitter signaling :: 1) Reuptake—transporter proteins pump neurotransmitter back into presynaptic neuron for recycling, 2) Enzymatic degradation—enzymes break down neurotransmitter in cleft (e.g., acetylcholinesterase), 3) Diffusion—neurotransmitter drifts away from cleft.

Why doesn't doubling neurotransmitter release double the postsynaptic response? :: Receptors saturate. Binding follows θ = [NT]/([NT] + Kd), which is hyperbolic. When most receptors are already occupied, adding more neurotransmitter produces diminishing returns. Synaptic strength is tuned by receptor number, vesicle release probability, and receptor sensitivity, not just neurotransmitter concentration.

Concept Map

Hinglish (regional understanding)