Synapses and synaptic transmission

Book pp. 981–987 · asked 3 times in NTRUHS papers

In one breath

A synapse is a junction where one neuron hands its message to the next, and in the CNS most synapses are chemical, axodendritic and many-to-one. The arriving action potential opens voltage-gated Ca²⁺ channels; Ca²⁺ makes docked, primed vesicles fuse (synaptobrevin on the vesicle gripping syntaxin in the membrane) and pour transmitter into a 20–50 nm cleft. The transmitter opens postsynaptic channels and makes a graded EPSP (toward depolarization) or IPSP (toward hyperpolarization). The soma adds these up, and if the sum reaches firing level (about +15 mV) an action potential starts at the initial segment.

Builds on: Neurons and glial cells · Leads to: Properties of synapses · Neurotransmitters

Synapses in the CNS

• A synapse is a junction between two neurons, where information passes from one to the other.
• Synapses carry messages to their right targets inside the CNS, and carry the CNS’s commands out to the peripheral organs.
• The higher functions (processing and integrating information, learning, memory) all rest on synapses switching on and changing.
• New synapses keep forming, and old ones keep being modified, throughout life.

Count	About
Synapses made by one neuron	2000
Neurons in the CNS	10¹¹
Synapses in all	2 × 10¹⁴
Synapses to neurons, human forebrain	40000 : 1

Types of synapses

By the parts that meet

Type	Contact	How common
Axodendritic	axon → dendrite	commonest
Axosomatic	axon → cell body	next most common
Axoaxonic	axon → axon	less common
Dendrodendritic	dendrite → dendrite	rare

• An axodendritic ending may land on a dendritic spine (an axospinous synapse) or on the shaft of the dendrite (a shaft synapse).
• In the cerebral cortex about 80% of synapses are on dendrites and only about 15% on cell bodies.

By how the signal crosses

Type	Signal crosses by
Chemical	release of a neurotransmitter
Electrical	gap junctions
Conjoint	partly electrical, partly chemical

By how many neurons take part

Pattern	Where you find it
One to one	neuromuscular junction; parasympathetic ANS
Many to one	the usual pattern in the CNS
One to many	less frequent; sympathetic ANS

Functional anatomy of a synapse

The rest of this page is about the chemical synapse: it is the common kind, and electrical synapses are few in the CNS.

• The neuron that sends the message is presynaptic; the one that receives it is postsynaptic.
• The synapse itself has three parts: the presynaptic terminal (its membrane is the presynaptic membrane), the synaptic cleft, and the postsynaptic membrane.

Presynaptic terminal

• The axon ends in a small swelling, the terminal bouton or synaptic knob. Your book gives its diameter as about 1 mm.
• It contains many synaptic vesicles loaded with transmitter, dense tufts, and a few large mitochondria.
• Worth knowing, though not in your pages: a knob is about 1 µm across; “1 mm” is a misprint, since a millimetre is larger than the whole cell body.

Synaptic vesicles come in three kinds:

Vesicle	Carries
Small, clear core	ACh, GABA, glycine, glutamate
Small, dense core	catecholamines
Large, dense core	neuropeptides

• Large vesicles lie all through the terminal and can be released from any part of its membrane.
• Small vesicles sit near the membrane and are released through the active zone. After emptying they are recycled, in six steps:
  1. The emptied vesicle is coated with clathrin and pinched off from the membrane.
  2. The coat is shed and the vesicle merges with an early endosome.
  3. A new vesicle buds from the endosome and is refilled with transmitter.
  4. It docks at the active zone.
  5. It is primed.
  6. It releases its transmitter by Ca²⁺-triggered exocytosis.

Dense tufts are projections of filamentous protein, in contact with the vesicles and with larger filaments in the axoplasm. They sit mainly in the active zone and help drive exocytosis.

The active zone is a patch of presynaptic membrane specialised for release. It is crowded with proteins and Ca²⁺ channels, and most transmitter is released here.

Applied: autoreceptors

The presynaptic membrane has receptors of its own. They sense the transmitter their terminal has just released and adjust how much more comes out, which is why they are called autoreceptors. Usually they brake release when it runs high: α2 receptors, for example, hold back noradrenaline release. Occasionally they boost release instead.

Synaptic cleft

• The gap between the two membranes, 20–50 nm wide.
• It is filled with extracellular fluid, and the transmitter crosses it by diffusion to reach the receptors.

Postsynaptic membrane

• Usually part of a dendritic spine, sometimes part of the soma or an axon. It carries the receptors for the transmitter.
• The patch built for transmission is the postsynaptic density: a dense cluster of receptors set into the membrane.
• The transmitter amplifies the incoming signal. Released from one small ending, it spreads over a wide area of postsynaptic membrane and opens many receptor channels, so a presynaptic spike can drive the postsynaptic neuron.

Specific binding proteins hold receptors in clusters facing the releasing terminal:

Receptor	Binding protein
Glutamate receptors	”PB2-binding protein” (as printed)
GABA-A receptors	gephyrin
Nicotinic ACh receptors	rapsyn

• Worth knowing, though not in your pages: the anchoring protein usually named for glutamate (NMDA) receptors is PSD-95.

Neurexins

• Proteins fixed in the presynaptic membrane that bind neurexin receptors in the postsynaptic membrane.
• By tying the two membranes together they keep the synapse’s structure stable, and the orderly layout of a synapse depends partly on them.
• Three genes, each with α and β forms, two regulatory regions and much alternative splicing of its mRNA, give more than 1000 different neurexins.
• They are thought both to hold synapses together and to make each synapse specific.
• Worth knowing, though not in your pages: your book also says a single gene makes neurexin “in many vertebrates”, which clashes with its own three-gene count; a single neurexin gene is the pattern in invertebrates such as the fruit fly. Neurexin’s main postsynaptic partner is neuroligin.

Draw it: a chemical (axodendritic) synapse

1. At the top, an axon ending in a rounded synaptic knob. Inside it draw small round vesicles (some dotted with transmitter), two or three mitochondria, and short strands of dense tufts near the lower membrane.
2. Thicken the knob’s lower membrane and label it the active zone. Put a Ca²⁺ channel in it with a Ca²⁺ arrow pointing in, and show one vesicle fusing and spilling transmitter.
3. Below it, a narrow gap labelled synaptic cleft, 20–50 nm.
4. At the bottom, a dendritic spine whose membrane has a dark thickening, the postsynaptic density, studded with receptors: ion channels, and one receptor linked to a G protein.
5. Add a small autoreceptor on the knob, and label the two sides presynaptic and postsynaptic neuron.

Steps of synaptic transmission

At a chemical synapse the message crosses in two halves: events in the terminal (presynaptic) and events in the receiving cell (postsynaptic).

Presynaptic mechanisms

1. Docking and priming. Vesicles gathered at the active zone attach to the membrane (docking) and are made ready to empty the moment a stimulus arrives (priming).
2. Depolarization. The action potential reaches the terminal and depolarizes its membrane.
3. Ca²⁺ entry. Voltage-gated Ca²⁺ channels open, and Ca²⁺ flows in through the active zone.
4. Exocytosis. The rise in Ca²⁺ makes the microfilaments of the dense tufts contract, which moves the vesicles into the membrane; they fuse and empty into the cleft.
5. Quantal release. Transmitter comes out in fixed packets (quanta) and diffuses passively across the cleft. From Ca²⁺ entry to release takes about 200 µs.

• Kiss-and-run: a vesicle may empty through a tiny pore that closes again at once, so the vesicle itself stays inside the terminal. Some vesicles are then taken back and refilled on the spot, a short cut through the usual recycling.

"Dale's phenomenon"

Your book says quantal release is sometimes called Dale’s phenomenon. Don’t confuse it with Dale’s principle, which says a neuron releases the same transmitter from all of its endings. Release in quanta was shown by Bernard Katz and his colleagues. In the exam, call it simply quantal release.

Membrane proteins in release

Protein	Where it sits	Its job
Synaptobrevin	vesicle membrane (v-SNARE)	grips syntaxin
Syntaxin	terminal membrane (t-SNARE)	grips synaptobrevin
SNAP-25	bound to syntaxin	helps the pairing
α/γ SNAPs	bound to synaptobrevin	help the pairing
rab3	a small GTPase	regulates the protein complex
Clathrin	coat of the emptied vesicle	brings it back in

• The synaptobrevin–syntaxin grip is what docks and primes a vesicle and lets it fuse when Ca²⁺ rises.

Clinical significance: toxins

Many neurotoxins stop synaptobrevin binding syntaxin, so vesicles cannot fuse and no transmitter is released. Botulinum toxin comes in seven types, A to G.

Toxin	Protein it attacks
Botulinum A and B	SNAP-25 (as printed)
Botulinum C	syntaxin
Botulinum B, D, F, G	synaptobrevin
Tetanus toxin	synaptobrevin

• Botulinum toxin stops ACh release at the neuromuscular junction, so the muscles go limp: flaccid paralysis.
• Tetanus toxin stops transmitter release at synapses inside the CNS, and the result is spastic paralysis.
• Worth knowing, though not in your pages: tetanus toxin travels back up motor axons into the spinal cord and silences the inhibitory interneurons there (which use glycine and GABA), so the motor neurons fire unchecked.

A slip in your book: botulinum B

Your book puts B both with A (on SNAP-25) and with D, F and G (on synaptobrevin). B attacks synaptobrevin. The types that cleave SNAP-25 are A and E; C cleaves SNAP-25 as well as syntaxin. In the exam, “A on SNAP-25, C on syntaxin, B, D, F and G on synaptobrevin” agrees with both your book and the standard texts.

Applied: botulinum toxin as a medicine

In small doses it relaxes overactive muscle. Injected into the lower esophageal sphincter it relaxes the sphincter in achalasia cardia, and low doses relax facial muscles to smooth wrinkles.

Postsynaptic mechanisms

1. The transmitter binds its receptor and changes the receptor’s shape. The receptor then either opens an ion channel or sets off a chain of reactions that makes a second messenger, which in turn changes the membrane’s permeability to ions.
2. Transmitter that drifts off the receptors is cleared: it is broken down by enzymes or taken back into the presynaptic terminal.
3. Ions move through the opened channels. Depending on which ion moves (cation or anion) and which way, the membrane shifts toward depolarization or hyperpolarization. This shift, the synaptic potential, is the signal in the postsynaptic neuron.

The whole chain: action potential in the terminal → Ca²⁺ enters → vesicles fuse → transmitter crosses the cleft → binds receptors → channels open → EPSP or IPSP.

Applied: desensitization

Receptors exposed to a ligand for a long time grow less responsive to it.

• Homologous desensitization is a weaker response to that same ligand. A long excess of catecholamines blunts β receptors: β-adrenergic receptor kinase (β-ARK) phosphorylates the receptor’s carboxyl end, and β-arrestin binds it and damps it down. Your book counts four β-arrestins, which also promote endocytosis.
• Heterologous desensitization is a weaker response to other ligands after long exposure to one.

Synaptic potentials

• A synaptic potential lasts longer than an action potential. An excitatory one can make the initial segment fire repeatedly.
• There are two kinds, the EPSP and the IPSP.

	EPSP	IPSP
Direction	toward depolarization	toward hyperpolarization
Book’s example	−70 → −60 mV	−70 → −80 mV
Real size	0.5–2 mV each	about 0.5 mV
Latency	about 0.5 ms	not given
Peak (as printed)	11.5 ms	11.5 ms
Excitability	raised	lowered
Transmitters	ACh, noradrenaline	GABA, glycine
Ionic basis	Na⁺ or Ca²⁺ in; K⁺ channels shut	Cl⁻ in; K⁺ out; Na⁺ or Ca²⁺ channels shut
Slow form	↓ K⁺ conductance	↑ K⁺ conductance

EPSP

• A shift of the postsynaptic membrane toward depolarization, for example from −70 to −60 mV.
• It starts about 0.5 ms after the afferent impulses enter the spinal cord, rises to a peak and then falls away exponentially.
• One EPSP moves the membrane only 0.5–2 mV, but EPSPs from many knobs add together, and an EPSP of the right size excites the neuron.
• It is called excitatory because, while it lasts, the neuron responds more readily to other stimuli.
• Ionic basis: Na⁺ or Ca²⁺ channels open and those ions flow in; closing K⁺ channels does the same job.
• Slow EPSP: seen in autonomic ganglia and cortical neurons. Latency 100–500 ms, lasting several seconds, usually from a fall in K⁺ conductance.

IPSP

• A shift toward hyperpolarization, for example from −70 to −80 mV (an IPSP of −10 mV in the book’s example), although a real IPSP moves the membrane only about 0.5 mV.
• While it lasts, the neuron responds less readily to other stimuli. Like the EPSP it is local and can summate.
• Made by GABA and glycine; it peaks and then falls away exponentially.
• Ionic basis: Cl⁻ channels open and Cl⁻ flows in down its concentration gradient; or K⁺ channels open and K⁺ flows out; or Na⁺ or Ca²⁺ channels close.
• Slow IPSP: also seen in autonomic ganglia and cortical neurons, usually from a rise in K⁺ conductance.

A slip in your book: "11.5 ms"

Your book says both potentials peak at 11.5 ms. Standard texts put the EPSP’s peak about 1–1.5 ms after it begins, so “11.5” is most likely “1–1.5” with its dash lost, and the IPSP figure looks like the same slip. In the exam, “latency about 0.5 ms, peak within 1–1.5 ms” is safe.

Reversal potential

• The equilibrium potential for Cl⁻, E(Cl), is about −70 mV. At that voltage Cl⁻ has no net push either way, so opening Cl⁻ channels moves no charge.
• If the membrane sits less negative than −70 mV (say −50 mV), Cl⁻ flows in and the membrane hyperpolarizes: an ordinary IPSP.
• If it sits more negative (say −90 mV), Cl⁻ flows out and the membrane depolarizes: the response has reversed.
• The voltage at which the response flips, here −70 mV, is the reversal potential.

Reading the reversal-potential paragraph

Your book’s wording is tangled. Its “less than −70 mV, e.g. −50 mV” means less negative, and at −90 mV the outflow of Cl⁻ makes the inside less negative, not positive. Its last line also reads as if −90 mV were the reversal potential. The reversal potential is the voltage where the Cl⁻ current stops and changes direction, −70 mV here: above it Cl⁻ flows in, below it Cl⁻ flows out.

Draw it: EPSP and IPSP

Draw a time axis (ms) and a voltage axis marked −80, −70 and −60 mV. Run a flat resting line at −70 mV. After a stimulus arrow and a short latency, draw a small hump up toward −60 mV that decays back: the EPSP. On a second trace, a small dip down toward −80 mV that decays back: the IPSP. Add a dashed firing level about 15 mV above rest, and note that only summed EPSPs reach it.

Genesis of the action potential

A postsynaptic neuron gets endings from many presynaptic neurons, anywhere on its soma and dendrites, and excitatory and inhibitory inputs keep arriving together.

1. All the EPSPs and IPSPs spread passively (electrotonically) and add together. Your book prints “electronically”.
2. The soma integrates them: what counts is their algebraic sum, depolarizing inputs minus hyperpolarizing ones.
3. If the net change is depolarizing and reaches about +15 mV, the neuron hits its firing level and a propagated spike begins.
4. The full action potential arises only at the initial segment, the part of the neuron with the lowest threshold.

• From there the spike runs two ways: orthograde, down the axon to its terminals, and retrograde, back into the soma. The retrograde wave clears the soma, ready for the next round of synaptic input.
• Worth knowing, though not in your pages: the initial segment has the lowest threshold because it is packed with voltage-gated Na⁺ channels.

	Synaptic potential	Action potential
Arises at	dendrites and soma	initial segment
Size	graded, small	full spike
Spread	local	propagated both ways
Duration	longer	shorter

• Worth knowing, though not in your pages: the action potential is all-or-none and, because of its refractory period, cannot summate the way synaptic potentials do.

Where graded potentials arise

EPSPs and IPSPs are graded potentials, and they arise where the synapses are: mostly on the dendrites, and on the soma. The all-or-none spike starts at the initial segment. Asked where a neuron makes its graded potentials, answer the dendrites, not the axon hillock or initial segment.

Role of dendrites

1. Dendrites widen the surface on which knobs can land; the more dendrites, the better the neuron integrates excitation and inhibition.
2. The number and pattern of dendritic spines change during development. A neural protein that your book calls “neurolignin” (neuroligin) controls how synapses form.
3. Spines change during learning and long-term potentiation. A few dendrites have been found to start propagated action potentials themselves.
4. Protein synthesis happens not only in the soma but also on ribosomes in the spines, and it can change the effect of glutamate inputs.

• Spines are not fixed. New ones can sprout and grow, or vanish, within minutes to hours. Strands of mRNA carried out from the soma drive protein synthesis in the dendrite, remodel the spine and change the strength of its synapses.
• Such spine changes are thought to underlie motivation, learning and long-term memory.

Electrical synapses

• Here the two membranes come very close and are joined by gap junctions: low-resistance channels that ions cross easily, so electrical activity passes directly from one neuron to the next.
• Electrical synapses are sparse in the CNS.
• Worth knowing, though not in your pages: each gap-junction channel is a pair of connexons, one from each cell, and each connexon is a ring of six connexin proteins.

Feature	Chemical	Electrical
Crosses by	transmitter across a cleft	ions through gap junctions
Direction	usually one way	both ways
Latency of the EPSP	longer	shorter
Time to cross	longer	much shorter
Signal	can be magnified or modified	not magnified
In the CNS	the common type	sparse

• Because a chemical synapse can magnify and shape the signal, your book counts it the better design for transmission.

Exam-answer skeleton: "Define a synapse, classify synapses, and describe synaptic transmission, with EPSP and IPSP" (long essay)

1. Define a synapse and say why synapses matter in the CNS.
2. Classify: by the parts involved, by the mode of transmission, and by the number of neurons.
3. Functional anatomy, with a labelled diagram: knob, vesicle types, dense tufts, active zone, cleft (20–50 nm), postsynaptic density.
4. Presynaptic events: docking and priming, depolarization, Ca²⁺ entry, exocytosis through the SNARE proteins, quantal release.
5. Postsynaptic events: receptor binding, ion channels or second messengers, clearing of the transmitter.
6. EPSP and IPSP: definitions, values and ionic basis, with the comparison table and a sketch of both traces.
7. Summation at the soma and firing at the initial segment.
8. Close with how inhibition is produced (direct and presynaptic; see Properties of synapses) and a line on electrical synapses.

Asked in exams

• Where a neuron makes graded potentials: Aug 2024, MCQ
• Synaptic transmission: EPSP, IPSP and inhibition: Aug 2017, 10 marks · Oct 2024, MCQ