Neurophysiology & Synapses

Drawn from this guide's own material, each ending on its exam trap. Nothing loads from YouTube until you tap one.

• Graded Potentials and Summation in 90 SecondsWatch · 1:49

  Exam trap: An IPSP can inhibit without moving Vm · Open Cl⁻ channels shunt every EPSP

  Practice it → Curves: Graded potentials and summation
• The Chemical Synapse, Step by Step in 90 SecondsWatch · 1:51

  Exam trap: Myasthenia: POSTsynaptic · worse with use · Lambert-Eaton: PREsynaptic · improves with use

  Practice it → Diagram: The chemical synapse, step by step

Mechanisms, curves, and what happens when each one fails.

• The chemical synapse in five steps. (1) The AP invades the presynaptic terminal; (2) voltage-gated Ca2+ channels open, and Ca2+ entry is the trigger — transmitter release scales steeply with it; (3) synaptic vesicles fuse via the SNARE apparatus and release transmitter; (4) transmitter diffuses across the cleft and binds postsynaptic receptors — ionotropic (a channel opens in milliseconds) or metabotropic (a G-protein cascade, slower and longer-lasting); (5) the signal is TERMINATED by reuptake, enzymatic degradation, or diffusion. Nearly every synaptic drug and toxin maps to exactly one of these steps — file each new agent by its step.
• Electrical synapses exist and are the exception. Gap junctions couple cells directly — bidirectional, essentially no delay, no transmitter. In humans they matter in cardiac muscle, single-unit smooth muscle, and some brain circuits. The chemical synapse's ~0.5 ms delay (Ca2+ entry and vesicle fusion) is the price paid for amplification, one-way traffic, and the ability to be excitatory, inhibitory, or modulated — which is why it's the rule and gap junctions the exception.
• EPSPs and IPSPs. An EPSP is a graded DEPOLARIZATION — the transmitter opened channels pulling Vm toward a potential above threshold (classically non-selective cation channels, as at nicotinic and glutamate receptors). An IPSP is a graded hyperpolarization or clamping — Cl− channels (GABA-A, glycine) or K+ channels (GABA-B, via G proteins) pulling Vm toward ECl or EK. Note the subtlety the exam enjoys: with ECl ≈ −70, opening Cl− channels may not move a resting cell at all, yet still inhibits it by shunting — holding Vm near −70 against every EPSP's effort.
• Summation — the neuron's arithmetic. One EPSP almost never reaches threshold. TEMPORAL summation: the same input fires repeatedly, each EPSP arriving before the last decays. SPATIAL summation: different inputs arrive together and add. The axon hillock (initial segment) integrates them — it has the highest voltage-gated Na+ channel density and thus the lowest threshold, so IT decides whether the neuron fires. Inputs synapsing close to the hillock outvote distal dendritic ones, because graded potentials decay with distance.
• The neuromuscular junction — the model synapse. One motor axon, one muscle fiber, one transmitter (ACh), one receptor (nicotinic, ionotropic), and — uniquely — a safety factor so large that every motor-nerve AP normally triggers a muscle AP: the end-plate potential is far suprathreshold. ACh is terminated by acetylcholinesterase in the cleft (not reuptake of ACh itself; choline is recycled). Because transmission is obligatory here, ANY pharmacologic or immune interference shows up as weakness — which is why the NMJ has a named disease or drug for every synaptic step.
• The NMJ's disease-per-step map. Presynaptic Ca2+ channels: Lambert-Eaton syndrome (antibodies; weakness that IMPROVES with repeated use as Ca2+ accumulates; paraneoplastic with small cell lung cancer). Vesicle fusion: botulinum toxin cleaves SNAREs (descending flaccid paralysis; also the cosmetic and therapeutic agent). Postsynaptic receptor: myasthenia gravis (antibodies deplete nicotinic receptors; fatigable weakness, worse with use — ptosis and diplopia by evening). Degradation: cholinesterase inhibitors (neostigmine, pyridostigmine) raise cleft ACh — the myasthenia treatment; organophosphates do it irreversibly — the poisoning. Receptor blockade: curare-type neuromuscular blockers used in anesthesia.
• The transmitter table worth owning. Glutamate — the CNS's main excitatory transmitter (AMPA fast, NMDA the coincidence-detecting, Ca2+-passing, Mg2+-plugged receptor behind synaptic plasticity and excitotoxicity). GABA (brain) and glycine (cord) — the main inhibitors, via Cl−; benzodiazepines, barbiturates, and alcohol potentiate GABA-A. ACh — NMJ, all autonomic ganglia, parasympathetic targets, and attention/memory circuits (Alzheimer target). The monoamines, each from a nameable nucleus: dopamine (substantia nigra/VTA — movement, reward; Parkinson, antipsychotics), norepinephrine (locus ceruleus — arousal; sympathetic postganglionics), serotonin (raphe — mood, sleep; SSRIs). Learn each as transmitter → receptor family → terminator → one drug and one disease.
• Termination decides the drug list. ACh is degraded in the cleft (acetylcholinesterase — hence cholinesterase inhibitors); the monoamines are RECAPTURED (reuptake transporters — hence SSRIs, SNRIs, cocaine's mechanism at the dopamine transporter) and mopped up by MAO/COMT (hence MAO inhibitors); glutamate is cleared largely by astrocytes (the glutamate-glutamine cycle — its failure contributes to excitotoxic injury in stroke). If you know how a transmitter's action ends, you can usually derive the drug class that prolongs it.
• Plasticity — why repetition is not a slogan. Synaptic strength is adjustable: brief high-frequency use potentiates some synapses for the long term (LTP — NMDA receptors admit Ca2+ only when the postsynaptic cell is already depolarized, a molecular AND-gate), and low-frequency use depresses others (LTD). This is the accepted cellular substrate of learning and the physiologic argument for spaced active recall over rereading. It also has a dark side: too much glutamate signaling kills neurons (excitotoxicity).

Each with the one fact that identifies it. Your course's slides are the authority; use this to check your list against.

1. 1Voltage-gated Ca2+ channel (presynaptic) — its Ca2+ entry is the trigger for transmitter release
2. 2SNARE proteins — dock and fuse synaptic vesicles; cleaved by botulinum toxin
3. 3Ionotropic receptor — transmitter-gated ion channel; milliseconds fast (nicotinic, GABA-A, AMPA)
4. 4Metabotropic receptor — G-protein-coupled; slower, longer-lasting (muscarinic, GABA-B)
5. 5Synaptic delay — ~0.5 ms for Ca2+ entry and vesicle fusion; absent at gap junctions
6. 6EPSP — graded depolarization toward threshold; classically a non-selective cation channel opening
7. 7IPSP — graded hyperpolarization or shunting via Cl− or K+ channels
8. 8Shunting inhibition — open Cl− channels clamp Vm near ECl even without visibly hyperpolarizing
9. 9Temporal summation — one input firing rapidly; EPSPs stack before decaying
10. 10Spatial summation — simultaneous inputs from different synapses add together
11. 11Axon hillock / initial segment — lowest-threshold zone, densest Na+ channels; the neuron's decision point
12. 12End-plate potential — the NMJ's giant EPSP; normally always suprathreshold (the safety factor)
13. 13Nicotinic ACh receptor — ionotropic cation channel at the NMJ and all autonomic ganglia
14. 14Acetylcholinesterase — terminates ACh in the cleft; the myasthenia-treatment and organophosphate target
15. 15Myasthenia gravis — antibodies deplete postsynaptic nicotinic receptors; fatigable weakness, worse with use
16. 16Lambert-Eaton syndrome — antibodies against presynaptic Ca2+ channels; weakness that improves with use
17. 17Botulinum toxin — cleaves SNAREs, blocking vesicle release; descending flaccid paralysis
18. 18Tetanus toxin — blocks transmitter release from INHIBITORY interneurons; spastic paralysis
19. 19Glutamate — the CNS's main excitatory transmitter; AMPA and NMDA receptors
20. 20NMDA receptor — Mg2+-plugged, Ca2+-passing coincidence detector; plasticity and excitotoxicity
21. 21GABA — the brain's main inhibitory transmitter; benzodiazepines potentiate GABA-A
22. 22Glycine — the spinal cord's inhibitory transmitter; blocked by strychnine
23. 23Dopamine — substantia nigra and VTA; movement and reward; Parkinson's missing transmitter
24. 24Norepinephrine — locus ceruleus and sympathetic postganglionics; arousal and vigilance
25. 25Serotonin — raphe nuclei; mood and sleep; the SSRI target
26. 26Reuptake transporter — ends monoamine signaling; the SSRI/SNRI and cocaine site
27. 27Long-term potentiation — high-frequency use strengthens a synapse via NMDA-admitted Ca2+

The distinctions that lose points on this material, year after year.

• Myasthenia vs Lambert-Eaton — which side of the cleft, which direction with use. Both are autoimmune NMJ weakness; the exam separates them on two hinges. Myasthenia is POSTsynaptic (receptors) and fatigues WITH use — receptors are scarce, so repeated stimulation runs the response down (evening ptosis). Lambert-Eaton is PREsynaptic (Ca2+ channels) and IMPROVES with use — repetitive firing accumulates terminal Ca2+, squeezing out more ACh (and it travels with small cell lung cancer). Swap either axis and you've picked the distractor.
• Botulinum and tetanus toxins both cleave SNAREs — and produce opposite pictures. The mechanism is shared; the TARGET NEURON differs. Botulinum acts at the NMJ and cholinergic terminals: no release, FLACCID paralysis. Tetanus toxin travels retrograde to spinal inhibitory interneurons and silences the inhibition of motor neurons: unopposed firing, SPASTIC paralysis — trismus and opisthotonus. 'Same molecule class, opposite disease' is precisely why examiners love the pair.
• An IPSP doesn't have to hyperpolarize to inhibit. With ECl sitting near the resting potential, opening GABA-A channels may move Vm barely at all — students conclude 'no effect.' Wrong: the open Cl− conductance shunts depolarizing current, so concurrent EPSPs shrink and threshold is never reached. Inhibition is about pulling Vm toward (and anchoring it at) a sub-threshold potential — not about the direction of the initial deflection.
• The end-plate potential is not an action potential. The EPP is a graded potential — decremental, produced by ligand-gated (not voltage-gated) channels, confined to the end plate. It normally TRIGGERS a muscle AP because the safety factor makes it hugely suprathreshold — which is exactly what myasthenia erodes. Questions that show a 'reduced but present end-plate response with no muscle contraction' are testing whether you keep the two events separate.
• Ionotropic vs metabotropic is a speed-and-duration axis, not an importance axis. Students rank 'direct channel' receptors as the real ones and G-protein receptors as minor. The autonomic nervous system runs almost entirely on metabotropic receptors (every muscarinic and adrenergic receptor), as do most psychiatric drug targets. Sort receptors by time course — milliseconds/ionotropic vs hundreds of milliseconds-to-minutes/metabotropic — and expect a vignette clue about speed or persistence.
• More transmitter is not always more signal. Organophosphate poisoning floods the cleft with ACh — and after initial overactivity, the depolarized end plate INACTIVATES its Na+ channels and receptors desensitize: depolarizing blockade, weakness, respiratory failure. The same logic runs succinylcholine's paralysis. It's the synaptic rerun of the hyperkalemia paradox: sustained depolarization silences excitable tissue.

Where this unit shows up again — in clinic, on rotations, and on the boards.

• Myasthenia gravis at the bedside. Fatigable ptosis and diplopia worse through the day, improving with rest or ice; diagnosed with receptor antibodies and decremental response on repetitive nerve stimulation; treated with pyridostigmine (more cleft ACh) and immunotherapy. Watch for myasthenic crisis with respiratory weakness — the NMJ's safety factor, gone.
• Organophosphate poisoning. An agricultural exposure with salivation, lacrimation, urination, defecation, bronchorrhea, miosis, bradycardia — then muscle fasciculations giving way to weakness: irreversible cholinesterase inhibition flooding every cholinergic synapse. Atropine blocks the muscarinic storm; pralidoxime rescues the enzyme before it 'ages.' The vignette is a tour of everywhere ACh acts.
• Botulism vs tetanus, clinically. Botulism: canned food or an infant's honey, descending flaccid paralysis starting with cranial nerves (diplopia, dysphagia), afebrile, pupils often dilated. Tetanus: a puncture wound, then trismus, risus sardonicus, and painful extensor spasms. Both are SNARE-cleaving clostridial toxins; the target neuron writes the opposite exams.
• Benzodiazepines, barbiturates, and alcohol share a receptor. All three potentiate GABA-A Cl− current (benzodiazepines increase opening FREQUENCY, barbiturates opening DURATION — a classic discriminator), which is why they cross-react: alcohol withdrawal is treated with benzodiazepines, and combining the classes depresses respiration synergistically. Flumazenil antagonizes the benzodiazepine site specifically.
• Parkinson disease as a transmitter deficit. Degeneration of substantia nigra dopamine neurons — bradykinesia, rigidity, resting tremor. Treatment logic is pure synaptic physiology: replace precursor (levodopa, with carbidopa to keep decarboxylation out of the periphery), stimulate the receptor (agonists), or block the degraders (MAO-B, COMT inhibitors). Antipsychotics run the same synapse in reverse — dopamine blockade producing parkinsonism.
• SSRIs and the reuptake principle. Blocking the serotonin transporter prolongs serotonin's synaptic dwell time — the first-line pharmacology of depression and anxiety. The delayed onset (weeks) is itself a synaptic lesson: the benefit tracks receptor-level and plasticity adaptations, not the immediate transmitter rise. Cocaine applies the same mechanism to the dopamine transporter, with a different clinical story.
• Stroke and excitotoxicity. Ischemic neurons depolarize, dump glutamate, and fail to recapture it; NMDA receptors flood downstream cells with Ca2+, activating destructive enzymes — the penumbra's mode of death and the reason 'time is brain.' The same overactivation in miniature underlies the theory behind memantine (an NMDA blocker) in Alzheimer disease.