23418 ModelSystem Synapse Neurotransmitters
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Synapses,
neurotransmitters and neuromodulators
Lecture series
Model Systems in Neurobiology: From Molecules to Behaviour
Wintersemester 2007/2008
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Synapses:Electrical synapses
Chemical synapses
Neurotransmitters:
Underlying mechanisms of signal
transduction for electrial/ chemical synapses
Neuromodulators:
What is neuromodulation?
Levels of action
Outline
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Synapses
Contacts between neurons, or between neuron and muscle (neuromuscular
synapse, neuromuscular junction, in vertebrates: motor endplate) are called
synapses.
The term „synapse“ was introduced by the Oxford professor of physiologySir Charles Scott Sherrington (1857– 1952)
Synapses are distinguished depending on the nature of
transmission: electrical or chemical synapse.
A synapse consists of a presynaptic part and a postsynaptic part
Neuromuscular synapse: the axon terminal of the motoneuron
Neuromuscular synpase: the muscle is the postsynaptic part
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Axon
Dendrite
Dendrite
Electrical synapse
Types of contacts: Inferior olivary nucleus of the cat
Chemical synapse
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gap junctions = electrical synapses
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gap junctions = electrical synapses
Freeze-fracture through the electrical synapse
Face view through the presynaptic membrane
(each particle in the cluster represents a single connexon)
Side view
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Molecules of electrical synapses
current flow
Connexons, Connexins
(Innexins in invertebrate animals!)
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Electrical synapses
* first identified by E. Furshpan and D. Potter 1957 in the nervous system
of crayfish
* very small gap (3,5 nm), gap junctions,
Vertebrates: Connexins form pores (diameter 2 nm) between pre- and
postsynaptic cell, current can flow in both directions without a noticable
time delay
Invertebrates: Innexins, a different family of channel proteins
In principle, therefore, electrical synapses can conduct in both directions,
but rectifying (gleichrichtende) electrical synapses exist, and electrical
synapses can also be influenced by neuromodulators!
(for example, size difference between pre- and postsynaptic neuron
iinduces a rectifying property)
* Exchange of low molecular weight material through gap junctions (ions,
small dye molecules such as Lucifer yellow)
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after Furspahn and Potter 1957, 1959
Electrical Synaptic Transmission at a Giant Synapse in the Crayfish CNS
Electrical synapse
Presynaptic lateral axon
Postsynaptic motor axon
B. Stimulation of presynaptic fiber
Each cell reaches threshold and fires an action potential!
A. Experimental setup
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Where can electrical synapses be found?
* during development (all neuroblasts are electrically coupled)
* whenever speed is required (giant fibre systems in Crustaceans and Annelids,
(escape behaviour), or in vertebrates in the Ciliar ganglion,
eye muscles (rapid contractions).
* heart muscle fibres and muscle fibres of smooth muscleare connected via gap junctions
* most likely, electrical synapses exist in greater numbers in
the CNS than anticipated
(for example in the mammalian brain they may be involved insynchronizing neuron ensembles)
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Axon
Dendrite
Dendrite
Electrical synapse
Types of contacts: Inferior olivary nucleus of the cat
Chemical synapse
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Chemical synapses
* synaptic cleft, about 20 - 40 nm wide
* presynaptiv neuron releases transmitter via vesicles which diffuses
through the synaptic cleft to the postsynaptic cell where it binds to
specific receptor molecules and changes the state of (ion) conductivity
* amount of transmitter released is dependent on the membrane potential
of the presynaptic neuron
* chemical snapses are rectifying (gleichrichtend), and conduct only in
one direction with a time delay of about 1 ms
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StructureStructure of of
neuromuscularneuromuscular synapsesynapseFrogFrog
Source: From Neuron to Brain
Martin Nicholls Wallace,
Sinauer, Sunderland, Mass., USA
Longitudinal section through a portion of neuromuscular junctionLongitudinal section through a portion of neuromuscular junction
PRESYNAPTICPRESYNAPTIC
POSTSYNAPTICPOSTSYNAPTIC
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Quantal release shown first
from Katz and Miledi,1952 on
frog neuromuscular junction
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Miniature endplate potentials of the frog neuromuscular synapse
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Quantal nature of transmitter release(Katz und Miledi 1952)
miniature endplate potentials
(„miniatures“, mEPPs)
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* mEPPs in unstimulated synapses (0,4 to 1 mV amplitude) can only be recorded in theimmediate vicinity of the end plate
* Estimates show a change in membrane potential of 0,3 µV as a consequence of a currentflow through one open ACh-channel. This means that for an endplate potential of 0,5 mVabout 5000 AChR have to be activated
* All EPSPs/IPSPs are manyfolds of a single mEPP (quantum)
* If the Calcium concentration of the presynapse changes the size of the quantum remainsconstant, however the probability of its release changes(if Ca-concentration is increased: failures decrease, and the probability of the simultaneous
release of two quanta increases)
* At the neuromuscular synapse one AP releases approx. 150 transmitter quanta, at centralsynapses between 1 and 10
Quantal nature of transmitter release
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Synapses of the giant axons in lamprey (Neunauge)
unstimulated
60 min after stimulation
stimulated, 15 min at 20 Hz
Do depleted synaptic vesicles melt with the membrane ordo they pinch back after release into cytoplasm?
After vigorous stimulation synaptic membrane area is
increased!
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Life cycle of synaptic vesicles
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The vesicles fuse by interactions between proteins of the vesicle
membrane and the cell membrane
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Interactions of vesicular membrane proteins and proteins of thepresynaptic cell membrane during the process of exocytosis
From Neuron to Brain, 4th edition, Nicholls,Martin, Wallace, Fuchs, Sinauer Associates, Sunderland, Mass., USA
SNARE Hypothesis
SNARE = named after SNAP receptor, first identified recepetor protein involved in exocytosis processSNARE = protein complex within active zone that is responsible for vesicle fusion with membrane and exocytosis
negative regulator
GTPase
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* Two different receptor molecules:
* ionotropic receptors are ion channels with a binding sitefor the respective transmitter, and cause fast changes inthe membrane potential of the postsynaptic neuron (in therange of milliseconds)
* metabotropic receptors activate a signaling cascade in thepostsynaptic cell which leads to slow changes in theelectrical (and also biochemical) properties of thepostsynaptic cell (in the range of hundreds of milliseconds, or seconds or even longer). Formation of an (intracellular) second messenger
Whether a transmitters is excitatory or inhibitory dependssolely on the properties of the postsynaptic receptor molecules.
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Ionotropic Receptor Metabotropic Receptor
e.g. nicotinic ACh-receptor e.g. muscarinic ACh-receptor
-pentamer of five subdomains (α,α,β, γ, δ) ACh binds to α subdomain
-all show a similar transmenbrane structure
αααα ααααSeven transmembrane proteinsthat activate other membrane associated proteins by
conformational change
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Neurotransmitters
acetylcholine (neuromuscular synapse of vertebrates, autonomic nervous system)
Biogenic amineshistaminecatecholamines: noradrenaline (norepinephrine), adrenaline (epinehrine), dopamineoctopamine (invertebrates)serotonin (5-hydroxytryptamine, 5-HT)
Amino Acidsγγγγ-aminobutyric acid (GABA), glycine, aspartateglutamate (neuromuscular synapse of invertebrates, important transmitter of the vertebratebrain)
PeptidesFMRF-amide, Proctoline, Opioids, Enkephalins, Endorphins, Dynorphin (endogenous Opioids)
Peptides of Neurohypophysis: Vasopressin, Oxytocin,Neurophysins, NeurotensinTachykinines: Substance P, Insulins, Somatostatin, Polypeptides of pancreas, Gastrines: Gastrin, Cholecystokinin
Gaseous TransmittersNitric oxide (NO), Carbon monoxide (CO)
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Synaptic plasticity:
Facilitation of transmitter release: Depression of transmitter release
e.g. Aplysia gill withdrawal reflex: homosynaptic depression leads to habituation and heterosynaptic fascilitation leads to sensitisation
Increase of postsynaptic response due to increase of Ca2+
in presynapse and therefore increased vesicle releaseDecrease of postsynaptic response due to decrease of Ca2+
in presynapse and therefore decreased vesicle release
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muscle muscle, or
other targets (e.g. glands, neurons)
neurotransmitter(„classical“ neurotransmitter)
* ionotropic postsynaptic receptors
fast action (milliseconds)* metabotropic postsynaptic receptors
slow but lasting action (seconds to hours)
neuromodulator
* metabotropic postsynaptic
receptorsslow but lasting action
(minutes to hours to days to weeks)
* specific targeted release
neurohormone
* released into hemolymph
global, systemic release* metabotropic postsnaptic receptors
* long lasting effects: months to years to life
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Neurotransmitter
Neuromodulator
Neurohormone
* „classical“ transmitter, released at synapses
(type I terminals), with fast postsynaptic response
(milliseconds), ionotropic receptor, opens ion channel
* transmitter, released at synapses with slow synapticresponse that lasts for longer time, metabotropic receptor,
signalling cascade, often co-transmitter, phosphorylation of
ion channels, (seconds to minutes to hours)
* modulator released from type II terminals (varicosities),
targeted release by special neurones, changing either
transmitter relase of other neurones or properties of postsynaptic neurones,
both pre- and postsynaptic metabotropic receptors,effects last a long time (minutes to hours to days to weeks)
phosphorylation of ion channels, other proteins, affecting
metabolic pathways, gene expression (learning, memory)
* transmitter released into circulatory system
(haemolymph, blood) by special neurosecretory cells,long lasting responses (months to years to life long)
metabotropic receptors or cytoplasmic receptors, controlgene expression and protein synthesis
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One of the most important excitatory (ionotropic/ metabotropic)
receptor: NMDA – receptor in vertebrate brain
Recepors are named after their agonist(e.g. NMDA: N-Methyl-D-Aspartate)
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Neuromodulation
“Modulator substance” is used for any compound of cellular or nonsynaptic origin that affects the excitability of nerve cells and
represents a normal link in the regulatory mechanisms that govern
the performance of the nervous system. Such modulator substances can affect the responsiveness of nerve cells to transsynaptic actions
of presynaptic neurones and they can alter the tendency to spontaneous activity“.
* an early definition by E. Florey (1967) Federation Proc. 26: 1164 – 1178
“Neuromodulation” occurs when a substance released from one neuron
alters the cellular or synaptic properties of another neuron“.
* Kupferman I (1979) Annu Rev Neurosci 2: 447-465 , Kacmarek LK and Levitan IB (1987) Neuromodulation..., Oxford University Press
“Any communication between neurons, caused by release of a chemical,
that is either not fast, or not point-to-point, or not simply excitation or inhibition
will be classified as neuromodulatory.“
* Katz P (1999) Beyond Neurotransmission...., Oxford University Press
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Neuromodulation
“Modulator substance” is used for any compound of cellular or nonsynaptic origin that affects the excitability of nerve cells and
represents a normal link in the regulatory mechanisms that govern
the performance of the nervous system. Such modulator substances can affect the responsiveness of nerve cells to transsynaptic actions
of presynaptic neurones and they can alter the tendency to spontaneous activity“.
* an early definition by E. Florey (1967) Federation Proc. 26: 1164 – 1178
A good working definition(of a 2004 Dahlem conference on microcircuits)
Neuromodulation is the targeted release of a substance
from a neuron (or glial cell ?) that either alters the
efficacy of synaptic transmission, or the
cellular properties of a pre- and/or postsynaptic neuron(or glial cell) via metabotropic receptors.
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Extrinsic neuromodulation
One form of intrinsic neuromodulation: Co-transmission
presynaptic neuron
postsynaptic neuron
neuromodulatory neuron
allows independent state definition (independent controller)
* separate control of neuromodulator release
automatic state definition (automatic controller)
* frequency and time dependent neuromodulator release
compartment of release
synapse
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BEHAVIOR: selection and induction of behavior (neuron ensembles, systems of networks)
Neuromodulators, Neurohormones
BIOMECHANICS/MUSCULATURE: execution of behavior (effector organs)Neuromodulators, Neurohormones
NEURONAL NETWORKS: rhythm, pattern generation, reconfiguration of networks
(affects timing, amplitude, phase), Neuromodulators (change synaptic gain,
electrical properties)
SINGLE NEURONS (elecrical properties)Neuromodulators (ionic currents)
SIGNALLING CASCADES (regulation of electrical
and biochemical properties incl. energy metabolism)
Neuromodulators
GENES AND PROTEIN BIOSYNTHESIS
(long term changes), Neuromodulators,
Neurohormones
Levels of Actions of Neuromodulators
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Fin
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Kandel ER (2001) Science 294, 1030-1038
Habituation
KiemenKiemen--RRüückziehreflex in ckziehreflex in
AplysiaAplysia californicacalifornica
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HabituationHabituation
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Habituation
200 ms
5 mV
10 mV
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Habituation / Adaptation
Habituation
ist die Abnahme der Reaktionsstärke auf einen
wiederholt einwirkenden Reiz.
Adaptation
ist die Abnahme der Reaktionsstärke auf einen
lang andauernden Reiz
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Quantal hypothesis of transmitter release (Fatt und Katz 1952)
* Each endplate potential, EPP, consists of a certain number of quanta
(a normal EPP has approximately 200 quanta), quantal content of an EPSP* reduction of quantal content by using solutions reduced in Ca2+ (less vesicles fuse)
* Del Castillo and Katz (1954): statistical analysis
* each motor terminal contains n quantal packages ACh, each of which is released
by the probability p.* If many eyperiments are performed, the mean quantal value released in each trial
is m and equals n p, and the number of events with 0,1,2,3,...x quanta would
correspond to a binomial distribution.
* If p is very small then the
number x of quanta should correspond to a Poisson-distribution:
nx = N (mx/x!) e –m
Problem: n and p are unknown and are not measurable, so the idea was to reduce the quantal release
by changing the extrcellular Ca2+ concentration
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Tsacopoulos and Magistretti, J. Neuroscience 16:877-885, 1996
Blutkapillare
Astrozyt
Neuropil:
Geflecht aus Dendriten und Axonen
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Tsacopoulos and Magistretti, J. Neuroscience 16:877-885, 1996