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Neurotransmission
Prof. Dr. Szabolcs Kéri
University of Szeged, Faculty of Medicine, Department of Physiology
2021
Why studying synapses?
Synaptopathy: diseases of the brain characterized by pathological synaptic structure and function
Key points
1. Synapsis: definition and classification
2. Signal transduction in the synapsis
3. Neurotransmitters: definition and classification
4. Important transmitter systems and their functions
5. Non-conventional transmission: axon – glial connection, retrograde signals, and volume transmission
1. Definition and classification of synapses
Definition and classification of synapses
Synapsis: Axons do not form a continuous network. They make contacts with dendrites or cell bodies. Synapse is a connection point to pass electrical or chemical signals to another neuron or to a target cell. A. CHEMICAL (neurotransmitter and receptor)B. ELECTRIC (gap junction)
I. Connection type:• Axodendritic• Axosomatic• Axoaxonal• Axomyelinic
II. Transmitter type and function:• Excitatory (Gray I: asymmetric, glutamate, spherical
vesicles)• Inhibitory (Gray II: symmetric, GABA, oval vesicles)• Modulatory (monoamines, small dense core vesicles)• Peptides (large dense core vesicles)
Posztszinaptikusdenzitás (PSD)
Gray IISymmetric GABA
Gray IAsymmetric Glutamate
Clear vesicles
Dense core vesicles
Axodendritic
Axosomatic
Axoaxonal
Spine synapse
Spine
Shaftsnapse
Postsynaptic density (PSD)
Outlook: molecular diversity of the synapses
2. Signal transduction in the synapse
Electric synapses: comparison with chemical synapses
ELECTRIC• Connexon pore (6 connexins)• Bidirectional diffusion of small molecules• Fast: minimal synaptic delay• Synchronization of neuronal groups• Glial networks• Passing second messengers (cAMP)
CHEMICAL• No pore in the membrane (transmitter and
receptor needed)• Synaptic delay (1-1.5 ms)• One-way (pre → postsynaptic)
Chemical neurotransmission
1. Transmitter stored in vesicles2. Action potential at the presynaptic terminal3. Opening of voltage-gated calcium channels4. Influx of calcium5. Calcium induces vesicle fusion6. Transmitter released into the cleft7. Transmitter binds to postsynaptic receptors 8. Opening of postsynaptic ion channel/activation
of second messengers9. Generation of inhibitory or excitatory
postsynaptic potentials (IPSP/EPSP)10. Transmitter elimination/inactivation (glial
uptake, presynaptic reuptake, enzymatic degradation)
11. Vesicle retrieval from presynaptic membrane (recirculation)
ASTROGLIA: TRIPARTITEsynapsis: pre-/postsynaptic + glia
1.
2.
3.
4.
5.
6.
7.
8.9.10.
11.
The mechanism of synaptic vesicle fusion
• Proteins implicated in vesicle fusion:▪ In the vesicle’s membrane: synaptobrevin,
synaptotagmin
▪ In the presynaptic membrane: SNAP-25, syntaxin
▪ Botulinum toxin (BOTOX) and tetanus toxin:
degradation of presynaptic proteins
• N-type voltage-gated presynaptic calcium channels (inhibited by omega-conotoxin)
• Quantal neurotransmitter release (neurotransmitter content of 1 vesicle = 1 quantum)
• Synaptic potentiation: higher postsynaptic response after high frequency presynaptic stimulation –calcium-calmodulin dependent protein kinase II → synapsin → docking of new vesicles
1. Vesicle docking –active zone
2. SNARE-complex
3. Calcium-synaptotagminbinding
4. Membran fusion, pore formation SNARE = SNAP Receptor
(Soluble NSF (N-ethymaleimide-sensitive factor) Attachment Protein Receptor)
Reuptake: Monoamines Acetylcholine
GABA Glutamate
Ionic mechanism of local potentials: postsynaptic potentials
EPSP (excitatory postsynaptic potential)• Local and graded depolarization of
the postsynaptic membrane• Influx of Na+ or Ca2+ into the
postsynaptic terminal• Excitatory transmitters: glutamate,
acetylcholine
IPSP (inhibitory postsynaptic potential)• Local and graded hyperpolarization
of the postsynaptic membrane • Influx of Cl- (GABA-A receptor) or
efflux of K+
• Inhibitory transmitters: GABA, glycine
Excitatorytransmitter
Depolarization
Electrotonic spreading
Inhibitory transmitter
Hyperpolarization
Cl-/K+
channel
Electrotonic currents
Postsynapticneuron
Axon hillock
EPSP + IPSPsummation
Spatial summation: Simultaneous EPSPs of many dendrites(EPSP 1-3) spreading to the cell body and summed at theaxon hillock → reaching the threshold, axon actionpotential (APA)
Depolarizing currents
Summed EPSP
Action potential
Temporal summation: EPSPs following each other intime are summed → reaching the threshold, axon actionpotential (APA)
Depolarizing currents
Summed EPSP
Actionpotential
Cell body: ganglion spinale(dorsal root ganglion cells) Cranial nerve ganglia (e.g. Gasserian ganglion)
Receptor cells, nerve terminal: graded receptor potential
Peripheral fiber (dendron)
Central fiber
Axon terminal(dorsal horn)
Transmitter release:glutamate, aspartate, SP/CGRP, other peptides, NO
Dorsal horn
Synapse
Receptor
Spinalganglion
Cellbody
Axon
The primary sensory neuron
Extracellularspace
Intracellularspace
Ion channelsclosed
Membrane streched, channels
open
Mechanosensitive cation channelsat the sensory nerve endings
Receptor potential: Influenced by stimulus strength,graded,local, spreading with decrement, depolarization → threshold →action potential
Threshold
Weak stimulus Moderate stimulus Strong stimulus
Receptorpotential
Receptorpotential
Receptorpotential
Actionpotential
Sensory nerve ending
Sensory transduction, receptor potential, and action potential
3. The definition and classification of neurotransmitters
The features of classic neurotransmitters
• Synthesized and present in the presynaptic terminal
• Released following depolarization and calcium-influx
• Specific receptors are present in the postsynaptic membrane
• Action is terminated by specific mechanisms (reuptake transporter in the presynaptic membrane, enzyme, glial uptake)
• Dale-principle: each axon terminal of a neuron releases the same transmitter • Co-transmitter: peptides released after high-frequency stimulation, inducing late
and prolonged EPSP• acetylcholine - vasoactive intestinal polipeptid (VIP)
• norepinephrine - neuropeptid Y (NPY)
• glutamate - substance P (SP)/calcitonin-gene related peptide (CGRP)
Classification of neurotransmitters
1. Acetylcholine
2. Amino acids (glutamate, glycine, GABA)
3. Biogenic amines (dopamine, noradrenalin, adrenalin, histamine, serotonin)
4. Peptides (opiates [endorphins, enkephalins, dynorphins], SP, CGRP, VIP)
5. Gases (NO, CO, H2S)
6. Lipids (endocannabinoids, prostaglandins)
7. Purines (adenosine, ADP, ATP)
Classification of neurotransmitter receptors: ionotropic and metabotropic
Ionotropic: ligand-gated ion channel Metabotropic: G-protein coupled receptors
1. Transmitter binding
2. Channelopening
3. Ion influx into the postsynaptic terminal
Postsynaptic
Synaptic cleft
1. Transmitterbinding
2. G-protein activation
3. G-protein subunit or second messenger modulates the ion channel
4. Ion channel opening
5. Ion influx
4. Organization and function of important transmitter systems
Transmitter Location of cell body Receptors Function
Acetylcholine • N. basalis Meynerti• Autonomic neurons• Motor endplate
• Ionotropic: nicotinic• Metabotropic:
muscarinic (M1-M4)
• Attention, memory• Sympathetic
preganglionic• Parasympathetic pre-
/postganglionic
Glutamate • Neocortex pyramidal cells (most abundant neurotransmitter)
• Ionotropic: NMDA, AMPA, kainate
• Metabotropic: mGluR1-R8
• General excitatory transmitter
• Learning, plasticity• Neurodegeneration
GABA (gamma-amino-butiric-acid)
• Neocortex interneurons• Purkinje-cells
(cerebellum)• Striatum
• Ionotropic: GABA-A/C• Metabotropic: GABA-B
• General inhibitory transmitter
• Cortical oscillation• Anxiety, vigilance
Glycine • Spinal cord• Brainstem
• Ionotropic: GlyR • Inhibitory transmitter
Acetylcholine and amino acid transmitters
Transmitter Location of cell body Receptors Function
Norepinephrine • Locus coeruleus• Sympathetic postganglionic
• Metabotropic: Alpha 1-2Beta 1-3
• Attention, vigilance, anxiety (alarm reaction)
• Sympathetic effect
Dopamine • Substantia nigra (pars compacta)
• Ventral tegmental area
• Metabotropic: D1-D5 • Reward, motivation• Movement control• Higher cognitive
functions
Serotonin • Raphe nuclei • Metabotropic: 5-HT1-2, 4-7
• Ionotropic: 5-HT3
• Emotional functions• Sleep, appetite, sex• Neuroendocrine
regulation
Histamine • N. tuberomammalis(posterior hypothalamus)
• Metabotropic: H1-4• Ionotropic: HisCl
(histamine-gated chloride channel)
• Sleep-wakefulness cycle, vigilance
• Appetite
Biogenic amines
DA
Thal/BG Limbic
Cortex
5HT – serotonin, NE – norepinephrine, DA – dopamineThal/BG – thalamus/basal ganglia
The functional organization of the brainstem monoaminergic systems
Three main targets:1. Thalamus/basal ganglia: vigilance,
movement control2. Limbic system (hippocampus,
amygdala): memory, emotions3. Prefrontal cortex: higher cognition
Dopaminergic neurons: histology and PET (positron emission tomography)
Function: improving signal-noise ratio in glutamate/GABA synapses
Imaging brainstem monoaminergic nuclei in humans(neuromelanin-sensitive MRI)
DOPAMINESubstantia nigraVentral tegmentalarea (VTA)
NOREPINEPHRINELocus coeruleus
Production, inactivation, and receptors of some key transmitters
Glucose → glutamine ↔ glutamate ↔ GABA
Glutamate decarboxylase (GAD) + vitamin B6
GABA → succinate, gamma-hydroxybutirate
The universal mechanism of re-uptake elimination of conventional transmitters:• Presynaptic: Na+-associated secondary active
symport• Uptake into the vesicles: H+-associated secondary
active antiport
1. The glutamate – GABA system
Glia
Glutamine
Glutamate
Glutamate
Glutamine
The most important receptors of the glutamate-GABA system
Inhibitory chloride-channel Excitatory non-selective cation-channel
GABAGABA
Benzodiazepin
Volatile anesthetics
Ethanol
Glutamate
Glycine
NMDA – N-methyl-D-aspartate
2. Acetylcholine and catecholamines (norepinephrine, epinephrine, dopamine)
3. Serotonin
• Production: tryptophan → 5-hydroxy-tryptophane → 5-hydroxy-tryptamine• Elimination:
▪ Presynaptic reuptake (SERT = serotonin transporter)▪ Enzymatic degradation: Monoamine Oxidase-A (MAO-A) (main metabolite: 5-
hydroxy-indolacetate)
4. Hisztamin
• Production: histidine → histamine• Elimination: rapid inactivation by Synaptic Histamine-N-Methyltransferase
Ionotropic receptorsCations• Nicotinic acetylcholine • Glutamate: NMDA, AMPA• Serotonin: 5-HT3Anion (chloride)• GABA-A/C • GlyR• HisCl
cAMP↑ (Gs)Norepinephrine: beta1-3Dopamine: D1,D5Histamine: H25-HT4-7
cAMP↓ (Gi)Acetylcholine: M2Norepinephrine: alfa2Dopamine: D2GABA-BmGLU5-HT1
IP3/DAG (Gq)M1Alfa1mGLUH15-HT2
cGMP ↑NO
Signal transduction of neurotransmitter receptors
Metabotropic receptors
AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
5. Non-conventional neurotransmission: axon-glia connection, retrograde signals, volume
transmission
The intraneuronal (axonal) transport
Cell body Axon
Synapse
KINESIN: anterogradetransport• Synaptic elements (e.g.
vesicles)• Peptide transmitters• Cytoskeleton
DYNEIN: retrograde transport• Degradation products• Neurotrophic signals• Neuroinvasive viruses (e.g.
herpes simplex)
Microtubule-associated proteins (e.g. tau) –neurodegeneration (e.g. Alzheimer’s)
Oligodendroglia
Axon
AMPA NMDA
The axomyelitic synapse
Classic and retrograde neurotransmission
1. CB1 receptor: endocannabinoid (EC) signal (anandamide, 2-arachidonoylglycerol)
2. NGF (nerve growth factor): retrograde trophic signal
3. NO (nitrogen monoxide)• Arginine → citrulline (neuronal NO-synthase,
NOS1)• cGMP – protein kinase G• S-nitrosylation (posttranslational
modification, e.g. cysteine)• NMDA-modulation• Direct effect on DNA• Reactive free-radical
Endo-cannabinoid
NO NGF
Classic Retrograde
Non-synaptic neurotransmission: volume transmission
• Neurotransmitter A and B diffuse to distant targetsoutside the synapse (1), and act on their receptors (2)• Extrasynaptic receptors, medication effects• Example: dopamine (DA) in the prefrontal cortex(link between higher cognition and motivation/attention)
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