Szinapszis ANGOL [ r sv dett]) · 2019.09.18. 3 Definition and classification of synapses Synapsis:...
Transcript of Szinapszis ANGOL [ r sv dett]) · 2019.09.18. 3 Definition and classification of synapses Synapsis:...
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Neurotransmission
Prof. Dr. Szabolcs Kéri
University of Szeged, Faculty of Medicine, Department of Physiology
2019
Why studying synapses?
Synaptopathy: diseases of the brain characterized by pathological synaptic structure and function
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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
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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)
Posztszinaptikus
denzitás (PSD)
Gray II
Symmetric
GABA
Gray I
Asymmetric
Glutamate
Clear vesicles
Dense core vesicles
Axodendritic
Axosomatic
Axoaxonal
Spine
synapse
Spine
Shaft
snapse
Postsynaptic density
(PSD)
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Outlook: molecular diversity of the synapses
2. Signal transduction in the synapse
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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 vesicles
2. Action potential at the presynaptic terminal
3. Opening of voltage-gated calcium channels
4. Influx of calcium
5. Calcium induces vesicle fusion
6. Transmitter released into the cleft
7. Transmitter binds to postsynaptic receptors
8. Opening of postsynaptic ion channel/activation
of second messengers
9. 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:
TRIPARTITE
synapsis: pre-
/postsynaptic + glia
1.
2.
3.
4.
5.
6.
7.
8.9.10.
11.
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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-
synaptotagmin
binding
4. Membran fusion,
pore formation SNARE = SNAP Receptor
(Soluble NSF (N-ethymaleimide-sensitive factor) Attachment Protein Receptor)
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
Excitatory
transmitter
Depolarization
Electrotonic spreading
Inhibitory transmitter
Hyperpolarization
Cl-/K+
channel
Electrotonic
currents
Postsynaptic
neuron
Axon hillock
EPSP + IPSP
summation
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Spatial summation: Simultaneous EPSPs of many dendrites
(EPSP 1-3) spreading to the cell body and summed at the
axon hillock → reaching the threshold, axon action
potential (APA)
Depolarizing
currentsSummed EPSP
Action potential
Temporal summation: EPSPs following each other in
time are summed → reaching the threshold, axon action
potential (APA)
Depolarizing
currents
Summed
EPSP
Action
potential
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
Spinal
ganglionCell
body
Axon
The primary sensory neuron
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Extracellular
space
Intracellular
space
Ion channels
closed
Membrane
streched, channels
open
Mechanosensitive cation channels
at 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
Receptor
potential
Receptor
potential
Receptor
potentialAction
potential
Sensory nerve ending
Sensory transduction, receptor potential, and action potential
3. The definition and classification of
neurotransmitters
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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).
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Classification of neurotransmitter receptors: ionotropic and metabotropic
Ionotropic: ligand-gated ion channel Metabotropic: G-protein coupled receptors
1. Transmitter
binding
2. Channel
opening
3. Ion influx into
the postsynaptic
terminal
Postsynaptic
Synaptic cleft
1. Transmitter
binding
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
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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
Transzmitter Sejttest helye Receptorok Funkció
Norepinephrine • Locus coeruleus
• Sympathetic postganglionic
• Metabotropic:
Alpha 1-2
Beta 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
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DA
Thal/BG Limbic
Cortex
5HT – serotonin, NE – norepinephrine, DA – dopamine
Thal/BG – thalamus/basal ganglia
The functional organization of the brainstem monoaminergic systems
Three main targets:
1. Thalamus/basal ganglia: vigilance,
movement control
2. Limbic system (hippocampus,
amygdala): memory, emotions
3. 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)
DOPAMINE
Substantia nigra
Ventral tegmental
area (VTA)
NOREPINEPHRINE
Locus coeruleus
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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
Reuptake: Monoamines Acetylcholine
GABA Glutamate
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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, PCP – phencyclidine (angel dust)
GluN1 (NR1),
GluN2 (NR2),
GluN3 (NR3),
subunits,
heterotetramer
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
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Ionotropic receptorsCations
• Nicotinic acetylcholine
• Glutamate: NMDA, AMPA
• Serotonin: 5-HT3
Anion (chloride)
• GABA-A/C
• GlyR
• HisCl
cAMP↑ (Gs)
Norepinephrine: beta1-3
Dopamine: D1,D5
Histamine: H2
5-HT4-7
cAMP↓ (Gi)
Acetylcholine: M2
Norepinephrine: alfa2
Dopamine: D2
GABA-B
mGLU
5-HT1
IP3/DAG (Gq)
M1
Alfa1
mGLU
H1
5-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, volumetransmission
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The intraneuronal (axonal) transport
Cell body Axon
Synapse
KINESIN: anterograde
transport
• 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
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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)
• Direct effect on DNA
• NMDA-modulation
• Reactive free-radical
Endo-
cannabinoid
NO NGF
Classic Retrograde
Non-synaptic neurotransmission: volume transmission
• Neurotransmitter A and B diffuse to distant targets
outside 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)