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Neurotransmitters and physiology of synapses Rostislav Tureček Institute of Experimental Medicine, CAS Department of Auditory Neuroscience [email protected]
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Neuronal communication 1) Electrical signals 2) Chemical signals Neurotransmitter (mediator): a substance that is released at a synapse by one neuron and that affects a postsynaptic cell in a specific manner.
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Thomas C. Südhof – Nobel Prize, 2013
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• Cells release neurotransmitters, usually stored in synaptic
vesicles in presynaptic endings. • Fast secretion of neurotransmitters is triggered in Ca2+-
dependent way. • Neurotransmitters diffuse from presynaptic to postsynaptic
cells across the synaptic cleft. • Neurotransmitters bind to postsynaptic cells at specific
sites – postsynaptic receptors – activate them and generate postsynaptic response.
Chemical signaling
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Syna
ptic
tran
smis
sion
Purves et al., Neuroscience, 5th ed., 2012
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Neurotransmitters (NT) Criteria:
- it is localized in the presynaptic neuron (biochemical or immunocytochemical evidence of NT or synthesizing enzymes), - it is released by presynaptic depolarization in Ca2+-dependent way (electrophysiological methods), - postsynaptic cell contains specific receptors for candidate NT (electrophysiological, biochemical or immunocytochemical methods, application of exogenous agonists or antagonists)
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Vesicular glutamate transporter (vGluT)- -positive terminals at central synapses
Guillaud et al., eLIFE 2017
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Immunohistochemical localization of glycine receptors in brain tissue C
onfo
cal m
icro
scop
y
Hru
skov
a et
al.,
J. N
euro
sci.
2012
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vGluT - peroxidase
GlyRs – immunogold particles
Imm
unoe
lect
ron
mic
rosc
opy
Hruskova et al., J. Neurosci. 2012
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Synt
hesi
s an
d st
orag
e of
NT
Purves et al., Neuroscience, 4th ed., 2008
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Two Major Categories of NT
1. Small-molecule mediators (low molecular weight, e.g. ACh, GABA, glutamate, serotonin, histamine) 2. Neuropeptides (high MW, contain several to tens of AA, e.g. substance P, neuropeptide Y, enkephalin) Co-transmitters – 1. together with 2. in the same nerve terminal.
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Differential synthesis of NTs
Purves et al., Neuroscience, 4th ed., 2008
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Co-transmitters examples: GABA/somatostatin ACh/substance P
small and clear SV (glutamate) large dense-core SV (neuropeptide) Purves et al., Neuroscience, 4th ed., 2008
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Synaptic vesicle cycle
Purves et al., Neuroscience, 4th ed., 2008
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Presynaptic release apparatus mediates fusion, Ca2+-triggering and Ca2+-channel tethering
Thom
as C
. Süd
hof,
2013
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Disturbances in SV exocytosis → neurological disorders
• myasthenic syndromes, defects in synaptic transmission at neuromuscular junctions (-> muscle weakness). Lambert-Eaton myasthenic syndrome (assoc. with lung cancer) – autoimmune reaction to presynaptic Ca2+ channels, reduced ACh release, imunosuppressive drugs
• Congenital myasthenic syndrome – failures in SV cycle - reduced ACh release, inhibitors of AChE
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Mechanisms of presynaptic Ca2+
clearance
Hammond, Cell. Mol. Neurophys, 4th ed., 2015
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Mechanisms of NT re-uptake
Specific transport proteins use presynaptic Na+ gradient
Vesicular transporters use electrochemical gradients: pH (ΔpH) and electrical (ΔΨ)
VanLiefferinge, Front. Cell. Neur. 2013
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Optogenetics: monitoring of SV and NT cycles
Kavalali, Nat. Neurosci., 2013
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Postsynaptic receptors Synaptic transmission: - fast: ligand-gated ion channels - slow: metabotropic receptors
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Ligand-gated ion channels
3 families: -cys-loop (GABA-A, GlyR, 5-HT, nAChR) -Glutamate (AMPA, KR, NMDA) -ATP (P2X)
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Fast synaptic transmission is typically studied using live brain slices
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Excitatory postsynaptic current (EPSC) and potential (EPSP)
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time
Mem
bran
e cu
rren
t Inhibitory postsynaptic current (IPSC) and potential (IPSP)
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Sum
mat
ion
of p
osts
ynap
tic
pote
ntia
ls
Purves et al., Neuroscience, 4thed., 2008
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Channelrhodopsin 2
Optogenetic techniques used to stimulate synaptic transmission
Nagel et al., PNAS, 2003
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Plasticity of synaptic transmission SV cycle vs. NT cycle - short-term plasticity vs. long-term plasticity
- presynaptic mechanisms vs. postsynaptic mechanisms
von Gersdorff and Borst, Nat. Rev. Neur. 2001
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Short-term depression – repeated stimulation of presynaptic neuron leads to transient depletion of synaptic vesicles. Gradual decrease of EPSC amplitude. Postsynaptic depression – desensitization of postsynaptic receptors Facilitation –high-frequency stimulation causes transient accumulation of Ca in presynaptic neuron and increase of presynaptic release probability.
High frequency synaptic transmission
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Silent synapses (NMDA-dependent LTP)
High-frequency stimulation – LTP. Low-frequency stimulation - LTD
Long term potentiation (LTP) and depression (LTD)
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Slow synaptic transmission and G-protein coupled receptors (GPCRs)
(GPCRs)
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Topology of GPCRs (heptahelical Rs) 7 TM domains, 3 extracellular (agonist binding site, low M) and 3-4 intracellular loops (G-protein interactions)
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GPCR classes - A (rhodopsin-like) (acetylcholine, amines, peptides) - B (secretin receptor family) (peptides, hormones) - C (mGluR/pheromone) (glutamate, GABA) - D (pheromone) - E (cAMP receptors) - Frizzled
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Neurotransmitters 1) Acetylcholine 2) Biogennic amines 3) Glutamate 4) GABA and glycin 5) Purines 6) Neuropeptides 7) Endocannabinoides 8) Gas mediators
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Acetylcholine -Neuromuscular junctions, ganglia of visceral motor system, CNS -Excitatory (mainly) and inhibitory effects -Precursors: Cholin + acetyl CoA -Inactivation: ACh esterase
Purves et al., Neuroscience, 4thed., 2008
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Acetylcholine receptors 1) Nicotinic, nAChR (ionotropic) agonist: nicotine (leaves of Nicotinia tabacum) antagonist: tubocurarine (bark of Chondrodendron tomentosum) 2) Muscarinic, mAChR(metabotropic) GPCR agonist: muscarine (Amanita muscaria) antagonist: atropine (Atropa belladona)
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Acetylcholine receptors 1) Nicotinic, nAChR (ionotropic) agonist: nicotine (leaves of Nicotinia tabacum) antagonist: tubocurarine (bark of Chondrodendron tomentosum) 2) Muscarinic, mAChR(metabotropic) GPCR agonist: muscarine (Amanita muscaria) antagonist: atropine (Atropa belladona)
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nAChR: Subunits: -α1-10 (agonist binding) -β1-4 -γ -δ -ε
Laviolette and van der Kooy, Nat. Rev. Neurosci 2004
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nAChR: Subunits: -α1-10 (agonist binding) -β1-4 -γ -δ -ε
Davis and de Fiebre, A
lcohol Res. H
ealth 2006
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Variable composition of native receptors: - Homopentamers of α7, α8, α9 – in CNS - Heteropentamers, e.g. α1β1ε(γ)δ – neuromuscular junction Embryonic (γ) vs adult (ε) - α2-10, β2-4 neuronal subtypes
nAChR:
Deranged Physiology 2015
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mAChR: 1. inhibit adenylyl cyclase
(α: M2, M4)
2. stimulate phospholipase C
(M1, M3, M5)
3. regulate ion channels
(βγ: M2, M4)
Deranged Physiology 2015
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2. stimulate phospholipase C
(M1, M3, M5)
mAChR:
Deranged Physiology 2015
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Neuromuscular junction
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Cholinergic synapse
Jones et al., Neuropsychopharmacology 2012
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Importance of cholinergic systems - Motor activity - Learning and memory: nucleus basalis - Alzheimer disease
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Glutamate – the main excitatory NT in CNS
Purves et al., Neuroscience, 4thed., 2008
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Ionotropic GluRs: cation permeable channels Subtypes: -NMDA (GluN1, GluN2A-D, GluN3A,B) -AMPA (GluA1-4) -Kainate (GluK1-5)
NMDAR
Staw
ski et al., Bioorg. M
ed. Chem
., 2010
Ghasemi and Schachter, Epilepsy&Behavior, 2008
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Metabotropic GluRs: GPCRs
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Glutamatergic synapse
Hammond, Cell. Mol. Neurophys, 4th ed., 2015
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Presynaptic glutamate receptors – spillover, autoreceptors vs. heteroreceptors, homosynaptic vs. heterosynaptic modulation
Presynaptic receptors
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GABA and glycine the main inhibitory NTs in the CNS
Purves et al., Neuroscience, 4thed., 2008
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Receptors for inhibitory aminoacids 1. Ionotropic (GABAA,C, glycine) - anionic channels (Cl-, HC03
-) - low [Cl- ]i - hyperpolarization, shunting of postsynaptic excitability
2. Metabotropic (GABAB) - GPCR - inhibition of AC or VDCC (presynaptic), activation of K+ channels (postsynaptic)
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Glycine receptor
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Glycine receptor
antagonist – strychnine (seeds of Strychnos nux-vomica)
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GABA-B receptor - GPCR
Padgett and Slesinger, Adv. Pharmacol, 2010
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GABAergic synapse
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Biogennic amines 1. Catecholamines: dopamine, epinephrine (= adrenaline) norepinefrine (= noradrenaline) 2. Histamine 3. Serotonin
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•Produced by nuclei concentrated in brainstem but terminals exhibit widespread distribution in the CNS •Mediate slow neurotransmission •Main function in CNS is neuromodulation
Ascending monoamine neurotransmitter systems. Figure shows schematic sagittal (A–D) sections through the lateral hypothalamus of a rat brain. (A) Origin and distribution of central noradrenergic pathways. Note noradrenergic cell groups A1–A7, including the locus ceruleus (A6).
(B) Origin and distribution of central dopamine pathways. Note dopaminergic cell groups A8–A10. Substantia nigra, VTA
(C) Origin and distribution of central cholinergic pathways. (D) Origin and distribution of central serotoninergic pathways. Note cell groups in the raphe nucleus, B4–B9. MFB, medial forebrain bundle; PFC, prefrontal cortex; VS, ventral striatum; DS, dorsal striatum.
Biogenic neurotransmitters
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Receptors for biogennic amines
Catecholamines: - Dopamine receptors - GPCRs, D1A,B, D2, D3, D4, activation or inhibition of AC - NE and epinephrine: α and β -adrenergic receptors, α1 - inhibition of K+ channels, α2 – activation of K+ channels or inhibition of AC, β1-3 – stimulation of AC
Histamine: H1 - H3, GPCRs, stimulation of PLC or AC
Serotonin: 5HT1-7, GPCRs except 5HT3 – ion channel permeable for cations, GPCRs – modulation of K+ channels, AC or PLC