Neurotransmission

Otto Loewi (1936)

Discovered chemical neurotransmission through his frog heart experiment; proved that nerves release a chemical messenger (Vagusstoff); Nobel Prize 1936.

Vagusstoff

The chemical substance (acetylcholine) released from the vagus nerve that slows heart rate; discovered by Otto Loewi.

Chemical neurotransmission

Communication between neurons via release of neurotransmitters into a synaptic cleft.

Electrical synapse

Direct ion flow between neurons through gap junctions, allowing very fast transmission.

Synapse

Junction between two neurons where neurotransmitters transmit signals across a synaptic cleft.

Bernard Katz (1970)

Proved neurotransmitters are released in quantal packets (vesicles); Nobel Prize 1970.

Quantal release

Theory that neurotransmitters are released in discrete vesicle packets; each quantum causes a miniature postsynaptic potential.

Miniature end-plate potential (MEPP)

Small postsynaptic depolarization caused by spontaneous release of a single neurotransmitter vesicle.

SNARE complex

Protein complex (synaptobrevin, syntaxin, SNAP-25) that mediates synaptic vesicle fusion with the membrane.

Botulinum toxin

Bacterial toxin that cleaves SNARE proteins, blocking acetylcholine release and causing flaccid paralysis.

Tetanus toxin

Cleaves synaptobrevin in inhibitory neurons, preventing GABA/glycine release and causing spastic paralysis.

Henry Dale

Coined the term neurotransmitter and established Dale’s principle (a neuron releases the same transmitter at all terminals).

Neurotransmitter criteria

Must be synthesized in neuron, released upon depolarization (Ca2+ dependent), mimic nerve stimulation, and have specific termination.

Presynaptic terminal

Part of neuron containing vesicles and release machinery for neurotransmitters.

Postsynaptic receptor

Protein on the receiving neuron that binds neurotransmitters to produce a response.

Synaptic cleft

Small gap (~20–30 nm) between neurons where neurotransmitters diffuse.

Acetylcholine (ACh)

Classical neurotransmitter released at neuromuscular junctions and in CNS; acts on nicotinic and muscarinic receptors.

Choline acetyltransferase (ChAT)

Enzyme that synthesizes acetylcholine from choline and acetyl-CoA.

Vesicular ACh transporter (VAChT)

Protein that packages acetylcholine into synaptic vesicles.

Acetylcholinesterase (AChE)

Enzyme in synaptic cleft that breaks down acetylcholine into choline and acetate.

Nerve gas (organophosphate)

Irreversible AChE inhibitor causing toxic accumulation of acetylcholine and muscle paralysis.

Neostigmine

Reversible AChE inhibitor used to treat myasthenia gravis.

Catecholamines

Class of neurotransmitters including dopamine, norepinephrine, and epinephrine derived from tyrosine.

Tyrosine hydroxylase

Rate-limiting enzyme converting tyrosine to L-DOPA in catecholamine synthesis.

DOPA decarboxylase

Converts L-DOPA to dopamine.

Dopamine β-hydroxylase

Converts dopamine to norepinephrine in vesicles.

Phenylethanolamine N-methyltransferase (PNMT)

Converts norepinephrine to epinephrine in adrenal medulla.

VMAT2

Vesicular monoamine transporter that loads dopamine, serotonin, and norepinephrine into vesicles.

DAT (Dopamine transporter)

Reuptake transporter removing dopamine from synaptic cleft.

NET (Norepinephrine transporter)

Reuptake transporter for norepinephrine.

MAO (Monoamine oxidase)

Mitochondrial enzyme that breaks down monoamines such as dopamine and serotonin.

COMT (Catechol-O-methyltransferase)

Cytosolic enzyme degrading catecholamines.

Cocaine

Blocks dopamine and norepinephrine reuptake transporters; increases synaptic monoamines and produces euphoria.

Amphetamine

Reverses monoamine transporters, increasing dopamine and norepinephrine release.

MAO inhibitor

Drug that prevents monoamine breakdown, increasing levels; used in depression and Parkinson’s disease.

β-blocker

Receptor antagonist that blocks β-adrenergic receptors; reduces heart rate and blood pressure.

Serotonin (5-HT)

Monoamine neurotransmitter derived from tryptophan; regulates mood, sleep, and appetite.

Tryptophan hydroxylase

Rate-limiting enzyme in serotonin synthesis.

SERT (Serotonin transporter)

Reuptake transporter that clears serotonin from synapse.

MAO-A

Isoform of MAO that preferentially metabolizes serotonin and norepinephrine.

SSRI (Selective Serotonin Reuptake Inhibitor)

Antidepressant that blocks SERT, increasing serotonin levels (e.g., fluoxetine, sertraline).

MDMA (Ecstasy)

Drug that reverses SERT and causes massive serotonin release; leads to euphoria and neurotoxicity with chronic use.

Triptans

5-HT1 receptor agonists used to treat migraine by constricting cerebral blood vessels.

Glutamate

Primary excitatory neurotransmitter in the brain; activates AMPA, NMDA, and kainate receptors.

AMPA receptor

Ionotropic glutamate receptor responsible for fast excitatory transmission.

NMDA receptor

Glutamate receptor requiring depolarization and glycine to open; allows Ca2+ influx important for synaptic plasticity.

Excitotoxicity

Neuronal death caused by excessive glutamate and calcium influx.

GABA (Gamma-aminobutyric acid)

Main inhibitory neurotransmitter in the brain, derived from glutamate.

Glutamic acid decarboxylase (GAD)

Enzyme that converts glutamate to GABA.

GABA-A receptor

Ligand-gated Cl- channel mediating fast inhibitory transmission.

GABA-B receptor

Metabotropic G-protein-coupled receptor mediating slow inhibition.

Benzodiazepine

Drug class that enhances GABA-A receptor activity; used as anxiolytics and sedatives.

Barbiturate

CNS depressant that prolongs GABA-A channel opening; used for anesthesia or seizures.

Long-term potentiation (LTP)

Long-lasting increase in synaptic strength; basis for learning and memory.

Hippocampus

Brain region critical for memory and learning; site of LTP studies.

NMDA-dependent LTP

Form of synaptic plasticity requiring NMDA receptor activation and Ca2+-dependent kinase signaling.

Substance P

Neuropeptide involved in pain transmission; found in sensory neurons.

Endorphins

Endogenous opioid peptides that reduce pain perception by acting on opioid receptors.

Vasopressin & Oxytocin

Neuropeptides that modulate stress, bonding, and social behaviors.

Nitric oxide (NO)

Gaseous neurotransmitter that diffuses freely across membranes; activates guanylyl cyclase.

Carbon monoxide (CO)

Gaseous neurotransmitter with regulatory roles in smooth muscle relaxation.

Termination of neurotransmission

Process by which signal ends via degradation, reuptake, diffusion, or autoreceptor feedback.

Autoreceptor

Presynaptic receptor that detects released neurotransmitter and inhibits further release.

Ionotropic receptor

Ligand-gated ion channel mediating fast synaptic responses.

Metabotropic receptor

G-protein-coupled receptor mediating slower, modulatory responses via second messengers.

Second messenger systems

Intracellular signaling cascades such as cAMP, IP3, DAG activated by metabotropic receptors.

Reuptake inhibitor

Drug that blocks transporter reuptake, increasing neurotransmitter levels in the synapse.

Storage blocker

Drug (e.g., reserpine) that depletes neurotransmitter vesicles by inhibiting VMAT.

Enzyme inhibitor

Drug that prevents neurotransmitter breakdown (e.g., MAO inhibitor, AChE inhibitor).

Receptor agonist

Drug that binds to and activates a receptor.

Receptor antagonist

Drug that binds to a receptor and blocks its activation.

Henry Dale’s principle

A neuron releases the same neurotransmitter at all of its terminals.

Südhof, Rothman & Schell (2013)

Received Nobel Prize for elucidating vesicle fusion and neurotransmitter release machinery.

Synaptic plasticity

Ability of synapses to strengthen or weaken over time, important for learning and adaptation.

Homeostasis in neurotransmission

Dynamic balance between excitatory and inhibitory inputs maintaining stable neural output.

Excitatory vs inhibitory balance

Concept that proper neural function requires balance between glutamate (excitation) and GABA (inhibition).

NMDA receptor blockers

Agents like ketamine or PCP that block NMDA channels; cause dissociative anesthesia and hallucinations.

SSRIs & SNRIs

Antidepressant drugs that block serotonin and/or norepinephrine reuptake to increase monoamine transmission.

Botulinum toxin clinical use

Used in small doses to treat muscle spasticity, dystonia, and cosmetic wrinkles.

Acetylcholinesterase inhibitors

Class of drugs enhancing cholinergic transmission; used in Alzheimer’s and myasthenia gravis.

GABAergic drugs

Agents enhancing inhibitory neurotransmission (e.g., benzodiazepines, barbiturates, alcohol).

Dopaminergic drugs

Agents that affect dopamine transmission; include antipsychotics (block D2) and stimulants (increase release).

Loewi’s frog heart experiment

Demonstrated that nerve stimulation releases a diffusible chemical messenger.

Katz quantal hypothesis

Established that neurotransmitters are released in discrete quanta (vesicles), not continuously.

Synaptic vesicle cycle

Sequence of vesicle docking, priming, fusion, release, and recycling.

Ca2+-triggered exocytosis

Process where calcium influx initiates vesicle fusion with the presynaptic membrane.

Reuptake transporters (DAT, NET, SERT)

Proteins that remove neurotransmitters from synaptic cleft; major target of psychoactive drugs.

Monoamine oxidase inhibitors (MAOIs)

Antidepressants that block monoamine degradation, increasing transmitter levels.

Cocaine & amphetamines

Psychostimulants that elevate dopamine and norepinephrine signaling by blocking or reversing transporters.

Selective receptor subtype

Different receptor isoforms for same neurotransmitter; allow tissue-specific drug targeting.

Beta-adrenergic receptors (β1, β2)

Receptors activated by epinephrine/norepinephrine; β1 affects heart, β2 affects bronchioles.

Atropine

Muscarinic ACh receptor antagonist used to dilate pupils and treat bradycardia.

Reserpine

VMAT inhibitor that depletes catecholamines; antihypertensive but can cause depression.

Synaptic delay

Time (~1 ms) between presynaptic depolarization and postsynaptic response due to chemical transmission steps.

Excitatory postsynaptic potential (EPSP)

Depolarizing potential that increases the likelihood of firing an action potential.

Inhibitory postsynaptic potential (IPSP)

Hyperpolarizing potential that decreases the likelihood of firing an action potential.

Postsynaptic integration

Summation of EPSPs and IPSPs determining neuron firing.

Synaptic fatigue

Decreased neurotransmitter release during prolonged stimulation due to vesicle depletion.

Kandel et al.

Demonstrated molecular mechanisms of learning and memory via synaptic plasticity; Nobel Prize 2000.

Chemical vs electrical signaling

Chemical allows modulation and diversity; electrical is fast but less flexible.