03 - Synapses

TARGET DECK: MED::I::Signaling Pathways in Health and Disease::Physiology::03 - Synapses

Synapses

Charles S. Sherrington, 1897 — Textbook of Physiology

“So far as our present knowledge goes, we are led to think that the tip of a twig of the arborescence is not continuous with but merely in contact with the substance of the dendrite or cell body on which it impinges. Such a special connection of one nerve cell with another might be called a synapse.”

Historical Context

The term synapse was introduced by the British neurophysiologist Charles S. Sherrington in 1897. At the time, it was known that neurons sent one-way electrical signals from the body to the axons, but the mechanism of signal conduction along the cell and between neurons was still unknown.

Camillo Golgi vs. Santiago Ramón y Cajal — a major scientific dispute:

• Golgi (inventor of the neuron staining technique): proposed the reticular theory — neurons form a continuous reticulum
• Cajal: proposed the neuron theory — neurons are individual, separate cells

The neuron theory was supported by anatomical data and by Wallerian degeneration, described by Augustus Volney Waller in 1850.

---

Wallerian Degeneration

Timeline of Wallerian Degeneration

• 5–30 min after injury: acute axon degeneration in both proximal and distal segments, mediated by extracellular ${\text{Ca}}^{2+}$ influx and activation of the ${\text{Ca}}^{2+}$-dependent protease calpain; followed by axonal retraction and formation of axonal bulbs
• 24–48 h: the distal axon remains morphologically stable and electrically excitable
• >72 h: rapid fragmentation and cytoskeletal breakdown along the full length of the distal axon, followed by increased glial influx (astrocytes, macrophages, Schwann cells in PNS) to clear remnants and promote proximal axon regeneration

What mediates acute axon degeneration in the first 5–30 minutes after nerve injury?

Extracellular Ca²⁺ influx and activation of the intracellular Ca²⁺-dependent protease calpain

Anki cloze

In Wallerian degeneration, after >72 h, {1:rapid fragmentation and cytoskeletal breakdown} occur along the full length of the distal axon.

---

Types of Synapses — Overview

Feature	Electrical Synapse	Chemical Synapse
Distance between membranes	4 nm	20–40 nm
Cytoplasmic continuity	Yes	No
Ultrastructural components	Gap-junction channels	Presynaptic vesicles, active zones; postsynaptic receptors
Agent of transmission	Ion current	Chemical transmitter
Synaptic delay	Virtually absent	Significant: ≥0.3 ms, usually 1–5 ms or longer
Direction	Usually bidirectional	Unidirectional

Functional Summary

• Electrical synapses: very rapid but stereotyped; send simple depolarizing or hyperpolarizing signals; no long-term modifications in the postsynaptic cell; found in heart, liver, smooth muscle, nervous system
• Chemical synapses: more variable signaling, complex behaviors; can mediate excitatory or inhibitory actions; effects last from ms to minutes; can amplify signals; most synapses in the brain are chemical

---

Electrical Synapses (Gap Junctions)

Structure

The specialized contact region at an electrical synapse is the gap junction:

• Separation between neurons: 4 nm (vs. 20 nm normal nonsynaptic space)
• Bridged by gap-junction channels — specialized proteins that conduct ionic current
• Each gap-junction channel = pair of hemichannels
• Each hemichannel = 6 identical subunits called connexins

Transmission Properties

Signal transmission at electrical synapses is analogous to passive propagation of subthreshold electrical signals along axons → also called electrotonic transmission.

Key properties:

• Latency between pre- and post-synaptic action potential is almost null
• An action potential in the presynaptic cell is not necessary to evoke a response in the postsynaptic cell (cytoplasmic continuity)
• Variation in $V_m$ in the postsynaptic cell is proportional to variation in $V_m$ in the presynaptic cell

Modulation of Gap Junction Channels

Different gap-junction channels in different cell types respond differently to modulatory factors:

• Some close in response to ↓ ICF pH or high ICF ${\text{Ca}}^{2+}$
• Some are voltage-sensitive
• Some are phosphorylated in response to activity of nearby chemical synapses

Functional Role

Electrical transmission is useful for orchestrating large groups of cells:

• Several small cells can act coordinately as one large cell
• Effective resistance of coupled network is relatively small → from Ohm’s law, synaptic current required to fire is large (tends to dissipate)
• Once threshold is surpassed, electrically coupled cells fire synchronously (voltage-activated ${\text{Na}}^{+}$ currents rapidly conducted between cells)
• Found between glial cells (astrocytes, Schwann cells) and between neurons

What is the gap distance at an electrical synapse, and what bridges it?

4 nm; bridged by gap-junction channels composed of pairs of hemichannels, each made of 6 connexin subunits

Anki cloze

Electrical synaptic transmission is also called {1:electrotonic transmission} because it resembles passive propagation of subthreshold signals along axons.

---

Chemical Synapses

Mechanism of Transmission

Overview

Chemical synaptic transmission depends on diffusion of a neurotransmitter across the synaptic cleft.

Presynaptic terminals typically contain 100–200 synaptic vesicles, each filled with several thousand molecules of neurotransmitter. Release occurs at specialized regions of the presynaptic membrane called active zones.

Steps of Chemical Synaptic Transmission

1. Presynaptic action potential → ${\text{Ca}}^{2+}$ influx via voltage-gated ${\text{Ca}}^{2+}$ channels
2. Rise in intracellular $[{\text{Ca}}^{2+}]$ triggers exocytosis (vesicles fuse with presynaptic membrane)
3. Neurotransmitter released into synaptic cleft
4. Transmitter diffuses and binds postsynaptic receptors
5. Ion channels open or close → altered membrane conductance and potential

Quantal Release (Katz)

Quantal Transmission

Katz and colleagues discovered that neurotransmitter is released in discrete amounts called quanta. Each quantum produces a postsynaptic potential of fixed size: the quantal synaptic potential.

Role of Ca²⁺

Calcium and Neurotransmitter Release

• ${\text{Ca}}^{2+}$ influx increases the probability that one quantum is released, without influencing the number of molecules inside each vesicle
• Two-fold increase in ${\text{Ca}}^{2+}$ influx → 16-fold increase in transmitter released
• Approximately 10–30 μM ${\text{Ca}}^{2+}$ is required to release the normal amount of neurotransmitter during an action potential
• Synaptic delay (1–2 ms) is largely due to the time required to open ${\text{Ca}}^{2+}$ channels(${\text{Ca}}^{2+}$ channels open more slowly than ${\text{Na}}^{+}$ channels); once ${\text{Ca}}^{2+}$ enters, transmitter is released within a few hundred microseconds

Why does a synaptic delay exist in chemical transmission?

Because Ca²⁺ channels open more slowly than Na⁺ channels; Ca²⁺ peaks during repolarization. Once Ca²⁺ enters, transmitter is released within a few hundred microseconds.

Anki cloze

A {1:two-fold} increase in Ca²⁺ influx can increase neurotransmitter release by {2:16-fold}.

Voltage-Gated Ca²⁺ Channels

Types of Voltage-Gated Ca²⁺ Channels Neurons contain five classes:

Type	Role at synapse
L-type	Muscle, endocrine cells
P/Q-type	Fast synaptic transmission (concentrated at active zone)
N-type	Fast synaptic transmission (concentrated at active zone)
R-type	Residual
T-type	Threshold/pacemaker

Structure of ${\alpha }_1$-subunit (pore-forming): homologous to the $\alpha$-subunit of voltage-gated ${\text{Na}}^{+}$ channel — 4 repeats of a domain with 6 membrane-spanning segments including the S4 voltage-sensor and pore-lining P region. Auxiliary subunits: ${\alpha }_2$, $\beta$, $\gamma$, $\Delta$.

Vesicle Recycling and Reserve Pool

Vesicle Pools The classic three-pool model:

• Reserve pool: 80–90% of total — vesicles outside active zone, regulated by synapsins
• Recycling pool: 10–15%
• Readily Releasable Pool (RRP): ~1% — docked and primed at active zone

Used vesicles are rapidly retrieved (usually clathrin-mediated endocytosis) and recycled to prevent depletion during high-frequency firing.

Synapsins Synapsins are substrates for both PKA and Ca²⁺/calmodulin-dependent protein kinase I. When the terminal is depolarized and ${\text{Ca}}^{2+}$ enters, synapsins are phosphorylated and released from vesicles, freeing them to join the active zone.

SNARE Proteins SNARE proteins are fundamental for vesicle fusion with the plasma membrane and exocytosis.

Vesicle cycle summary:

1. Import of neurotransmitter (via ${\text{H}}^{+}$/neurotransmitter antiporter, driven by ${\text{H}}^{+}$ gradient from ATP)
2. Movement to active zone
3. Docking at plasma membrane
4. ${\text{Ca}}^{2+}$-triggered exocytosis
5. Endocytosis via clathrin-coated vesicles

What are the three vesicle pools and their approximate proportions?

Reserve pool (80–90%), recycling pool (10–15%), readily releasable pool (~1%)

Anki cloze

SNARE proteins are fundamental for {1:vesicle fusion with the plasma membrane} and {2:exocytosis}.

Criteria for Identifying a Neurotransmitter

Three Required Criteria

1. Presence in the presynaptic terminal
2. Release due to presynaptic terminal depolarization
3. Postsynaptic receptors specific to the substance

Practical difficulties prevent these criteria from being fully applied at many synapses → many substances remain “putative” neurotransmitters.

---

Neurotransmitters

Chemical Classification

Classical Neurotransmitters

• Acetylcholine (ACh)
• Biogenic amines
  • Catecholamines: Dopamine (DA), Norepinephrine (NE)/Noradrenaline (NA), Epinephrine (EP)/Adrenaline (A)
  • Indolamines: Serotonin (5-HT), Histamine (H)
• Amino acids: GABA ($\gamma$-aminobutyric acid), Glycine, Glutamic acid

Non-Classical Neurotransmitters

• Neuropeptides (all receptors are G-protein linked):
  • Substance P — mediator of pain signals
  • Neuropeptide Y — stimulates appetite and food intake
  • Endogenous Opioids (Endorphins, Enkephalins, Dynorphin) — bind same receptors as opiates/morphine, reduce pain perception
• Novel messengers:
  • Nitric oxide (NO): same substance produced by sublingual nitroglycerin; short-lived gas; diffuses through membranes to bind intracellular receptor (guanylyl cyclase); also a free radical → highly reactive
  • ATP

ATP as Neurotransmitter (Purinergic Transmission)

• ATP stored in vesicles in nerve varicosities
• Released by exocytosis → acts on postjunctional P2 purinoceptors on smooth muscle
• Broken down extracellularly by ATPases and 5′-nucleotidase → adenosine
• Adenosine taken up by varicosities → resynthesized and stored
• Adenosine acts prejunctionally on P1 purinoceptors to modulate transmitter release
• Further breakdown by adenosine deaminase → inosine → removed by circulation

Functional Classification

Class	Effect	Example
Excitatory	Depolarization (EPSP)	Glutamate
Inhibitory	Hyperpolarization (IPSP)	GABA

Key Principle

A neurotransmitter may have both excitatory and inhibitory effects depending on the receptor type on the postsynaptic neuron. Example: ACh is excitatory at skeletal muscle (nicotinic receptors) and inhibitory at cardiac muscle (muscarinic receptors).

Receptor-Based Classification

• Ionotropic receptors: open ion channels → rapid responses
• Metabotropic receptors: activate G-proteins → second messengers → long-lasting effects

Synthesis and Transport

Small-Molecule Transmitters

• Enzymes synthesized in the cell body → slow axonal transport to terminal
• Precursors transported into terminal → neurotransmitter synthesized and packaged locally

Peptide Transmitters

• Neurotransmitter precursors and enzymes synthesized in cell body
• Fast axonal transport of vesicles containing enzymes and pre-peptide precursors
• Enzymes modify pre-peptides → peptide neurotransmitter
• Released, then degraded by proteolytic enzymes

Axonal Transport

Type	Speed	Cargo
Slow anterograde	0.2–8.0 mm/day	Enzymes, RNA
Fast anterograde	200–400 mm/day	Vesicles, mitochondria
Retrograde	—	Signals toward cell body

• Anterograde (towards synapse): mediated by kinesin
• Retrograde (towards cell body): mediated by dynein
• Uses microtubules (23–24 nm diameter) as rails
• Cytoskeleton components: microtubules (23–24 nm), neurofilaments (10 nm), microfilaments (5 nm)

What motors mediate anterograde vs. retrograde axonal transport?

Anterograde: kinesin; Retrograde: dynein

Anki cloze

Fast axonal transport travels at {1:200–400 mm/day} and carries {2:vesicles and mitochondria}; slow transport carries {3:enzymes and RNA}.

---

Postsynaptic Receptors

General Features

Common Biochemical Features of All Receptors

1. Transmembrane proteins spanning the entire lipid bilayer; extracellular portion recognizes and binds ligand
2. Exert effect by either:
   • Directly modifying gating of an ion channel (ionotropic)
   • Inducing metabolic effects that indirectly modify channel gating (metabotropic)

Ionotropic vs. Metabotropic

Feature	Ionotropic	Metabotropic
Structure	Several transmembrane subunits forming channel-pore	Single polypeptide with 7 α-helices (7-TM)
Speed	Fast synaptic transmission	Slow synaptic transmission
Mechanism	Direct channel gating	G-protein → second messengers
Duration of effect	Milliseconds	Seconds to minutes (or longer)

Metabotropic Receptors — Signal Amplification

Intracellular Amplification Cascade One messenger binds 1 receptor → activates ~10 G-proteins → each activates 1 adenylyl cyclase → each generates hundreds of cAMP → each cAMP activates 1 PKA → each PKA phosphorylates hundreds of proteins → millions of phosphorylated proteins total

Consequences:

1. Amplification is differentiated: each second messenger activates different pathways
2. Can affect gene expression, changing cell phenotype
3. Regulatory steps (allosteric + covalent phosphorylation) produce molecules that persist much longerthan the receptor activation itself

Why do metabotropic receptors produce longer-lasting effects than ionotropic receptors?

Because they trigger intracellular signaling cascades (G-protein → second messengers → kinases) whose products persist much longer than the receptor activation itself, and can affect gene expression.

Anki cloze

Metabotropic receptors are characterized by {1:7 transmembrane α-helices} and act through {2:G-proteins and second messengers}.

Bio-electrical Effects on the Postsynaptic Cell

Determinants of Ion Flux Effects The bioelectrical effect depends on:

1. Type of ion
2. Molecular characteristics of the channel
3. Resting state of the channel
4. Gating mechanism of the channel

Movement of the same ions through different channels can have different effects.

---

EPSPs and IPSPs

Excitatory Postsynaptic Potentials (EPSPs)

EPSPs

• EPSPs = depolarizing potentials that increase excitability
• Induced by opening of ion channels permeable to most cations (${\text{Na}}^{+}$, ${\text{K}}^{+}$, ${\text{Ca}}^{2+}$) with similar ease
• At the neuromuscular junction: ACh-gated channels open → large inward ${\text{Na}}^{+}$ current + small outward ${\text{K}}^{+}$ current → net inward current → depolarization
• The resulting current = excitatory postsynaptic current (EPSC)

EPSC vs. EPSP Time Course

• EPSC duration: ~1–2 ms (time channels are actually open)
• EPSP duration: longer; tail and decay rate reflect passive membrane properties (RC properties)
• In slow synaptic transmission, EPSP duration reflects biochemical process kinetics
• Long EPSP duration (relative to EPSC and action potentials) allows temporal summation

Reversal Potential $I_x=g_x\cdot (V_m-E_x)$

The potential at which there is no EPSP (or EPSC) = reversal potential. For excitatory synapses: reversal potential ≈ 0 mV (±10 mV)

Inhibitory Postsynaptic Potentials (IPSPs)

IPSPs

• IPSPs = usually hyperpolarizing potentials that inhibit firing
• Triggered by neurotransmitter binding → opening of ligand-gated channels permeable to only one ion: ${\text{Cl}}^{-}$ or ${\text{K}}^{+}$
• Reversal potential = Nernst potential of the carrying ion (typically negative relative to resting potential)
• Opening → outward current → hyperpolarization

What ion species carry IPSP currents, and why does hyperpolarization result?

Cl⁻ or K⁺; their Nernst potentials are more negative than resting membrane potential, so opening these channels causes an outward current and hyperpolarization.

Anki cloze

The reversal potential for excitatory synapses is approximately {1:0 mV (±10 mV)}.

Summation

Temporal and Spatial Summation A neuron fires an action potential only when the axon hillockreaches threshold. Individual EPSPs are small and distant from the hillock — summation is required.

• Temporal summation: a synapse fires at high frequency so the next EPSP arises before the previous one has decayed
• Spatial summation: multiple synapses active simultaneously; EPSPs reach the hillock approximately at their maximum

Firing Rate The firing rate = number of action potentials per second. The amplitude of the EPSP exceeding threshold is proportional to the firing rate induced. An increase in firing rate can only be obtained by exciting neurons during the relative refractory period (RRP):

• RRP is characterized by a hyperpolarizing ${\text{K}}^{+}$ outward current
• A stronger depolarizing inward current is needed to counteract it
• The stronger the inward current, the earlier a new action potential is fired

Anki cloze

{1:Temporal summation} occurs when a synapse fires at high frequency so that the next EPSP is generated before the previous one has decayed; {2:spatial summation} occurs when multiple synapses are simultaneously active.

---

Glutamate Receptors

Glutamate Receptor Types Glutamate has both ionotropic and metabotropic receptors:

Type	Transmembrane segments per monomer	Examples
Ionotropic (iGluR)	4	AMPA (GluR1–4), Kainate (GluR5–7, KA1–2), NMDA
Metabotropic (mGluR)	7	mGluR1–8

---

GABA Receptors

GABAA (Ionotropic)

GABA A Receptor

• Cl⁻ channel built from 5 monomers, each with 4 transmembrane segments
• Subunit types: α, β, γ
• Each subunit can bind different molecules:
  • Ethanol
  • Benzodiazepines (BDZ) — bind BDZ docking site
  • Barbiturates — bind barbiturate docking site

What type of channel is GABA-A, and what ions does it pass?

A ligand-gated Cl⁻ channel composed of 5 subunits (α, β, γ), each with 4 transmembrane segments

GABAB (Metabotropic)

GABA B Receptor

• Metabotropic receptor
• Dimer built from 2 monomers, each with 7 transmembrane segments
• Activates G-proteins through GABA(B)R2 subunit

Anki cloze

GABA-A is an {1:ionotropic} Cl⁻ channel; GABA-B is a {2:metabotropic} G-protein-coupled dimer.

---

Presynaptic Inhibition

Mechanism Presynaptic inhibition reduces neurotransmitter release from the presynaptic terminal before it can act on the postsynaptic cell.

Via ionotropic receptors (e.g., GABA-A, nicotinic AChRs, NMDA):

• Subthreshold depolarization → inactivates ${\text{Na}}^{+}$ and ${\text{Ca}}^{2+}$ voltage-dependent channels → reduces AP amplitude and ${\text{Ca}}^{2+}$ entry
• Hyperpolarization → blocks AP or reduces its amplitude

Via metabotropic receptors (e.g., GABA-B, muscarinic AChRs, adenosine receptors):

• Inhibit presynaptic ${\text{Ca}}^{2+}$ channels through G-protein $\beta \gamma$ subunits or via second messenger-activated protein kinase phosphorylation
• ↓ ${\text{Ca}}^{2+}$ inflow → ↓ vesicular release → reduced efficacy of excitatory synapses

How do metabotropic receptors mediate presynaptic inhibition?

By inhibiting presynaptic Ca²⁺ channels via G-protein βγ subunits or via second messenger-activated protein kinase phosphorylation, reducing Ca²⁺ influx and therefore neurotransmitter release.

---

Neuromuscular Junction (NMJ)

The Neuromuscular Junction

• The nicotinic ACh receptor (nAChR) is a non-specific cation channel permeable to both ${\text{Na}}^{+}$ and ${\text{K}}^{+}$; since the ${\text{Na}}^{+}$ gradient is larger, net inward Na⁺ currentprevails → endplate depolarization
• The endplate potential is always large enough to trigger an action potential near the endplate (where voltage-gated ${\text{Na}}^{+}$ channels are located)
• 1:1 synapse: every presynaptic AP produces a postsynaptic AP
• ACh is degraded by acetylcholinesterase (AChE) — a tetrameric protein on the postsynaptic membrane

Why is the neuromuscular junction called a 1:1 synapse?

Because every presynaptic action potential reliably triggers a postsynaptic action potential.

Pharmacology of the NMJ

1 — Endplate Interference

Depolarizing and Non-Depolarizing Blockers

Duration	Drug Examples
Short-acting	Mivacurium, Rocuronium, Vecuronium
Intermediate-acting	Atracurium, Cisatracurium
Long-acting	Tubocurarine, Metocurine, Pancuronium, Doxacurium, Pipecuronium

Agonists and Antagonists

• Agonists: occupy receptors and activate them
• Antagonists: occupy receptors but do not activate them; block activation by agonists

Nicotinic AChR agonists often share structural features with ACh (the choline moiety):

• Carbamylcholine (carbachol) and succinylcholine: choline-containing; resistant to AChE hydrolysis → prolonged activation
• Nicotine: activates nAChR at NMJ; primary physiological effects via CNS nAChRs (dopamine release → euphoria, ↓ anxiety) and autonomic ganglia nAChRs

2 — Inhibitors of Acetylcholinesterase

AChE Inhibitors AChE inhibition → ↑ amplitude + prolonged duration of postsynaptic response to ACh.

Drug	Properties
Physostigmine	Plant alkaloid; prototype anticholinesterase; crosses BBB → central action
Neostigmine	Synthetic; does not cross BBB → no CNS action
Organophosphorus compounds	Cross BBB; irreversibly modify AChE via covalent bond to serine residue; most potent/lethal; chemical warfare agents (nerve gases) and insecticides

Organophosphorus absorption:

• Respiratory system: seconds to minutes
• GI system: 30–90 minutes
• Skin: 12–18 hours

Toxidrome of Cholinesterase Inhibitors Nicotinic (peripheral) effects (skeletal muscle, adrenal medulla): Fasciculations, myoclonic jerks, hyperreflexia, muscle rigidity, weakness, tremor, paralysis; tachycardia, dysrhythmias, hypertension, mydriasis

Muscarinic (peripheral) effects (heart, exocrine glands, smooth muscle): Bradycardia, prolonged PR/QRS/QT, AV blocks, cardiac arrest; miosis, lacrimation, blurred vision; bronchospasm, bronchorrhea, respiratory arrest; excessive salivation, vomiting, diarrhea, urinary incontinence; diaphoresis

CNS (nicotinic + muscarinic) effects: Anxiety, headache, confusion, dizziness, emotional lability, delirium, toxic psychosis, restlessness, ataxia, insomnia, respiratory/circulatory depression, coma, seizures

Mnemonic — Muscarinic toxidrome (DUMBELS / SLUDGE) DUMBELS: Defecation/Diarrhea, Urination, Miosis, Bradycardia/Bronchospasm, Emesis, Lacrimation, Salivation/Sweating SLUDGE: Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis

What is the mechanism of organophosphorus compound toxicity?

Irreversible covalent modification (via a serine residue) of acetylcholinesterase → excessive enhancement of cholinergic neurotransmission at both muscarinic and nicotinic receptors

3 — Reducing ACh Release

Tetanus Toxin and Botulinum Toxins Both are zinc-dependent proteases that:

• Recognize gangliosides on the presynaptic membrane of motor neurons
• Enter nerve terminals by binding to synaptic protein domains exposed during exocytosis
• Specifically cleave SNARE proteins required for vesicle exocytosis

Toxin	Target SNARE protein	Effect
Tetanus toxin	Synaptobrevin	Inhibits inhibitory interneurons → spastic paralysis
Botulinum B, D, F, G	Synaptobrevin	Inhibits ACh release → flaccid paralysis
Botulinum C1	Syntaxin	Inhibits ACh release → flaccid paralysis
Botulinum A, E	SNAP-25	Inhibits ACh release → flaccid paralysis

Clinical/cosmetic uses of botulinum toxin:

• Strabismus: injection into overactive eye muscles suppresses aberrant spasms
• Botox: temporary treatment of facial wrinkles

What is the difference between tetanus toxin and botulinum toxin in terms of site of action and clinical effect?

Tetanus toxin inhibits inhibitory interneurons in the spinal cord → spastic paralysis; botulinum toxin inhibits ACh release at motor neuron terminals → flaccid paralysis. Both cleave SNARE proteins (synaptobrevin, syntaxin, or SNAP-25).

Anki cloze

Tetanus toxin cleaves {1:synaptobrevin} in inhibitory spinal interneurons, causing {2:spastic paralysis}; botulinum toxin cleaves SNARE proteins at motor neuron terminals, causing {3:flaccid paralysis}.

---

TLDR

Summary — Synapses

• Synapse coined by Sherrington (1897); neuron theory (Cajal) vs. reticular theory (Golgi); supported by Wallerian degeneration
• Wallerian degeneration: acute calpain-mediated axon degeneration (5–30 min); distal axon stable for 24–48 h; full fragmentation after 72 h with glial clearance
• Electrical synapses: gap junctions (connexins, 4 nm gap); electrotonic, bidirectional, near-zero delay; good for synchronization
• Chemical synapses: 20–40 nm cleft, unidirectional, 0.3–5 ms delay; mediated by neurotransmitter → receptor interaction; can amplify and produce long-term changes
• Neurotransmitter release: Ca²⁺-dependent (P/Q and N-type channels at active zones); quantal; 10–30 μM Ca²⁺ required; 2× Ca²⁺ = 16× release; delay due to slow Ca²⁺ channel opening
• Vesicle pools: reserve (80–90%, synapsins), recycling (10–15%), RRP (~1%, SNARE-dependent docking); recycled via clathrin endocytosis
• Neurotransmitter criteria: presence in terminal + release on depolarization + specific postsynaptic receptors
• Neurotransmitter classes: classical (ACh, catecholamines, indolamines, amino acids) and non-classical (neuropeptides, NO, ATP)
• Ionotropic receptors: multi-subunit ligand-gated channels; fast; EPSP (reversal ~0 mV) or IPSP (Cl⁻/K⁺ channels, reversal at Nernst potential)
• Metabotropic receptors: 7-TM GPCR; slow; massive signal amplification via G-protein → adenylyl cyclase → cAMP → PKA → gene expression changes
• Summation: temporal (high-frequency same synapse) and spatial (multiple simultaneous synapses) required to reach AP threshold at axon hillock
• Firing rate ∝ EPSP amplitude above threshold; increased by exciting during relative refractory period
• GABA-A: ionotropic Cl⁻ channel, 5 subunits, modulated by BDZ/barbiturates/ethanol; GABA-B: metabotropic dimer, 7-TM, G-protein coupled
• Glutamate receptors: ionotropic (AMPA, Kainate, NMDA — 4 TM segments) and metabotropic (7 TM segments)
• Presynaptic inhibition: via ionotropic (inactivates Na⁺/Ca²⁺ channels) or metabotropic receptors (βγ G-protein or kinase → ↓ Ca²⁺ channels)
• NMJ pharmacology:
  • AChE inhibitors (physostigmine crosses BBB; neostigmine does not; organophosphates — irreversible, warfare agents)
  • Non-depolarizing blockers (d-tubocurarine, rocuronium, etc.)
  • Botulinum toxin (flaccid paralysis, cleaves synaptobrevin/syntaxin/SNAP-25) vs. tetanus toxin (spastic paralysis, cleaves synaptobrevin in inhibitory interneurons)