Synaptic Transmission
overview of synaptic transmission
- synapse: specialized junction that mediates two adjacent excitable cells
- summary of excitatory synapse
- arrival: presynaptic action potential arrives at the axon terminus
- Ca2+ influx: action potential alters Ca2+ membrane permeability, causing an influx
- release: neurotransmitters released via exocytosis
- reaction: neurotransmitter binds and reacts with postsynaptic receptors
- activation: synaptic ion channels activated, producing a current
- potential: current produces a postsynaptic potential
- neurotransmitter targets
- local: postsynaptic cells across a synapse
- intermediate: postsynaptic cells in the local area
- distant: targets reached through the vasculature
- receptor types
- ionotropic: ligand-gated ion channels
- metabotropic: ligand-activated biochemical cascades (especially G proteins)
- some metabotropic cascades ultimately target ion channels
- in this way, these cascades can also be indirectly ionotropic
morphology of the synapse
- presynaptic and postsynaptic elements
- axo-somatic
- axo-dendritic
- dendro-dendritic
- axo-axonal
- synaptic cleft: gap between presynaptic and postsynaptic cell membranes (15-30 nm wide)
- express a high density of proteins specialized for synapse
- as such, carry a greater electron density than surrounding membranes
- synaptic bouton: enlarged axonal or dendritic terminal comprising the presynaptic element
- terminal contains large numbers of mitochondria, neurotransmitter-containing vesicles
- active zone: regions along the presynaptic membrane where vesicles cluster
- fast synaptic transmission: binding of neurotransmitter induces a conformational change that opens ion conductors
fast excitatory synaptic transmission
- neurotransmission
- processes
- diffusion: process by which neurotransmitter crosses synapse (small, measured in μs)
- receptors: have specific affinities for neurotransmitters (or related pharmacological agents)
- neurotransmitter specificity
- excitatory: glutamate increase permeability to Na+, K+, and sometimes Ca2+ ions
- inhibitory: GABA, glycine increase permeability to Cl- ions
- postsynaptic potentials (PSPs)
- excitatory (EPSP): brings Vm toward threshold (depolarization)
- inhibitory (IPSP): brings (or holds) Vm away from threshold
- EPSPs drive the membrane potential toward threshold
- excitatory postsynaptic potential (EPSP): graded, depolarizing potentials
- summation: many EPSPs are generally required to bring the postsynaptic neuron to threshold
- consequence: action potential in postsynaptic neuron will alter excitability of connected neurons
- the EPSP is a transient event
- rising: increase in PNa, PK
- falling: unbinding and removal (reuptake, digestion) of transmitter
- Vm changes are not instantaneous and depend on the time constant of the membrane
- time constant: time it takes Vm to change by 1/e of its original value
- time constant (τ): 
- Rm: membrane resistance (insulation properties)
- Cm: membrane capacitance
- characteristics
- typical values: τ =1-10 ms
- passive property of the membrane, not involving voltage-gated channels
- temporal and spatial summation of EPSPs drive Vm toward threshold
- quantitative depolarization
- release of one vesicle of an excitatory neurotransmitter: ~0.2 mV
- threshold required for action potential initiation: 10-20 mV
- required number of synaptic inputs for AP stimulation: 10-100
- summation and depolarization to threshold
- temporal summation: synaptic potentials arising close together in time
- membrane capacitance stores a “memory” of past potential that decays with τ
- with synaptic potentials less than ~5τ, potentials will summate
- most effective when time between events is short compared to τ
- spatial summation: synaptic potentials arising close together in space
- region between two nearby synapses firing simultaneously will experience charge from both synapses
- most effective when distance between events is short compared to λ
- spatiotemporal summation: synaptic potentials arising close together in space and time
- more realistic case
- note that EPSPs, IPSPs, and any combination of the two can summate to modulate depolarization
- summation and membrane resistance
- quantitative analysis
- time constant: 
- length constant: 
- both τ and λ depend on membrane resistance, so declining Rm will reduce effectiveness of summation
fast inhibitory synaptic transmission
- origin: GABA or glycine on ligand-gated ion channels permeable to Cl-
- action: clamp Vm near ECl, far away from the threshold (generally hyperpolarizing)
initiation of the action potential
- initiation: results from integration of the total constellation of excitatory and inhibitory inputs
- axon hillock
- determines overall excitability of the axon
- contains highest density of Na+ channels in the neuron, and thus is the point of lowest threshold
- backpropagating spikes: APs generated by cell bodies and dendrites after initiation at the axon hillock
- start at the hillock, and propagate back into the soma and dendrites
- do not violate unidirectional propagation, as that process refers to directionality from starting point
- possible consequences of summation of currents
- quiescence of the neuron
- isolated action potential
- train of repetitive action potentials
- localization
- excitatory synapses: generally located on distal dendrites
- inhibitory synapses: generally located more proximally (proximal dendrites, soma)
- more distally located synapses have greater influence on AP firing due to localization of current
presynaptic inhibition
- presynaptic inhibition: reduction in probability of a vesicle being released from individual axon terminals
- generally performed by axo-axonal synapses
- presynaptic axon inhibits a postsynaptic excitable axon
- common mechanism: increased permeability to Cl- ions
- shunts current of the AP, reducing its amplitude and duration (thus making this a “graded” response)
- Ca2+ influx is reduced, and less is available to mediate neurotransmitter release, diminishing the EPSP
types of transmitters
- types
- small molecule neurotransmitters
- examples: acetylcholine, glutamate, gamma-amino-butyric acid (GABA), glycine
- frequency: less frequent (10-15)
- peptide neurotransmitters
- examples: substance P, enkephalins, beta-endorphin
- frequency: more frequent (>50)
TABLE: Types of Neurotransmitters
| small-molecule neurotransmitters | peptides |
| glutamate, GABA, glycine (amino acids) norepinephrine (noradrenaline), dopamine serotonein histamine acetylcholine (ACh) ATP | substance P enkephalin lutenizing hormone RH (LHRH)
(more than 50 total) |
- classification as a neurotransmitter
- demonstrated to be present at the nerve terminal
- proven to be released upon terminal stimulation
- shown to have the same post-synaptic action when directly applied as that observed with presynaptic summation
synthesis and storage of transmitters
- small molecule neurotransmitters
- expression: tissue dependent
- synthesis: via cytosolic enzymes that have been transported to the synaptic terminal
- storage: small, clear vesicles
- specific carrier proteins in vesicular membrane load each neurotransmitter
- concentrations can reach 200 mM
- ATP required for vesicle loading
- localization: near synaptic active zone
- peptide neurotransmitters
- expression: tissue dependent
- synthesis: within endoplasmic reticulum
- processing: Golgi apparatus
- transport: secretory vesicles (axonal transport)
- storage: dense core vesicles (secretory vesicles)
- localization: periphery of the synaptic terminal
release of small molecule transmitters
- Ca2+ influx
- axon terminals have voltage-gated Ca2+ channels that open upon depolarization
- local [Ca2+] increases markedly
- Ca2+ channels are concentrated very close to the active zone (strong localization)
- ECa ≈ +130 mV (strong inward driving force)
- axon terminals have extremely small volumes on the order of fL (very low solution volume)
- neurotransmitter release
- probability of release
- 
- because of the steep relationship, only small changes in [Ca2+] are required to widely vary Pr
- duration of release
- as Pr implies, four Ca2+ ions must cooperatively bind to activate vesicular release
- channels exhibit little inactivation on the time-scale of fast synaptic transmission (0.1 to 1 ms)
- amount of transmitter released regulated largely by duration of the action potential
- modulations
- 4-aminopyridine (4-AP): blocks certain K+ channels, prolonging AP and thus neurotransmitter release
- presynaptic inhibition: often works through G-protein cascade that inhibits Ca2+ gating
- quantification
- quantal: release occurring in multiples of a fundamental unit
- vesicle: fundamental quantum (unit) of transmitter
- most synapses require multiple AP to release a vesicle
- some synapses (e.g. high frequency receptors in the ear) may release hundreds of vesicles with one AP
- molecular mechanism for release
- subject of enormous research
- synaptotagmin: activated upon binding Ca2+, somehow promotes fusion of vesicle to plasma membrane
termination of transmitter action (CNS)
- mechanisms
- diffusion: transmitters diffuse rapidly into the much larger extrasynaptic volume
- degradative enzymes: break down neurotransmitters
- acetylcholinesterase: breaks down ACh; one of the fastest, most efficient enzymes known
- neurotransmitter transporters: reuptake into cells (much slower)
- exist for GABA, serotonin, glutamate, catecholamines
- transporters are often drug targets
- cocaine: blocks dopamine reuptake
- antidepressants: block dopamine, norepinephrine reuptake
- seizure medication: blocks GABA reuptake
- mechanism: cotransport along with Na+, sometimes Cl-
recycling of vesicles by endocytosis
- importance
- vesicular release causes vesicle to fuse with cellular membrane
- in order to preserve structure and maintain store of releasable vesicles, vesicles must be retrieved
- clathrin: protein forming a coat around a vesicle, helping to retrieve it from the membrane
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