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Transcript of SYNAPTIC TRANSMISSION - u-szeged.hu · Compare transmission between electric and chemical synapses...
17. Neurotransmission.
Characterize electric synapses including the description of the molecular structure of gap junction
operating in these synapses. Compare transmission between electric and chemical synapses
(direction of information, speed of transmission).
Describe the consecutive events of chemical neurotransmission (starting with the depolarization of
presynaptic membrane ending with the development of the graded electric response of the postsynaptic
membrane (postsynaptic potential, PSP). Describe the ion currents involved in the development of the
following local potentials: excitatory postsynaptic potential (EPSP), inhibitory postsynaptic potential
(IPSP), end plate potential (EPP).
Describe the temporal and spatial summation of postsynaptic potentials (EPSPs and IPSPs), and their
role to trigger an action potential
Describe the common features of classical neurotransmitters.
Group the classical and non-classical neurotransmitters based on their chemical structure: 1. acetyl-
choline, 2. amino acids (glutamate, glycine, GABA), 3. biogenic amines (dopamine, noradrenaline,
adrenaline, histamine, serotonin), 4. gases (NO, CO), 5. lipids (endocannabinoids, 6. peptides
(endophins, encephalins, dynorphins, substance P, CGRP, VIP).
Characterize the neurotransmitters in bold based on their synthesis, inactivation, receptors and signal
transduction mechanisms. Define the terms ionotropic and metabotropic neurotransmitter receptors.
Describe the role of intraneuronal (axonal) transport mechanisms in the maintenance of interneuronal
communication.
Nonsynaptic neurotransmission. Volume transmission.
Normal values: synaptic delay: 1-1,5 ms.
"in recognition of their
work on the structure
of the nervous
system"
"for their discoveries
regarding the functions
of neurons"
"for their discoveries
relating to chemical
transmission of nerve
impulses"
”their discoveries relating
to the highly differentiated
functions of single nerve
fibres"
"for their discoveries concerning
the ionic mechanisms involved in
excitation and inhibition in the
peripheral and central portions
of the nerve cell membrane"
"for their discoveries concerning the
humoral transmittors in the nerve
terminals and the mechanism for
their storage, release and
inactivation".
"for their discoveries concerning the
peptide hormone production of
the brain" and the other half to
Rosalyn Yalow "for the development of
radioimmunoassays of peptide
hormones".
"for their discoveries concerning
signal transduction in the
nervous system"
"for their discoveries of machinery
regulating vesicle traffic, a major
transport system in our cells”
(mechanisms of exocytosis of
synaptic vesicles)
Santiago RAMON y
CAJAL
Camillo GOLGI
Nobel prize 1906
‘reazione nera’ (black reaction) of Golgi
“neuron doctrine” of Cajal
Santiago RAMON Y CAJAL: Histologie Du Systeme Nerveux de
L’homme et Des Vertébrés. (1909, Maloine, Paris)
• Histodynamic polarity
• Specificity of
connections (wiring)
THE NEURON DOCTRINE
von Waldeyer-Hartz (1891) is generally credited
with formulating the neuron doctrine, although as
soon as one writes that one is obliged to cite Cajal
(see Cajal 1954, for the English translation) who
wrote: ‘ Professor Waldeyer, to whom poorly
informed persons attribute the neuron theory,
supported it with the prestige of his authority but did
not contribute a single personal observation. He
limited himself to a short, brilliant exposition (1891)
of the objective proofs adduced by His, Kölliker,
Retzius, Van Gehuchten and myself, and he invented
the fortunate term of neuron’.
CONDUCTION OF THE NERVE IMPULSE
Du Bois-Reymond (1877): ”Of known natural processes that
might pass on excitation, only two are, in my opinion, worth
talking about - either there exists at the boundary of the
contractile substance a stimulatory secretion…; or the
phenomenon is electrical in nature“
Electric stimulation
Of the vagus nerve
Perfusion fluid
Electric stimulation
Perfusate
Otto LOEWI’S experiment proved the chemical nature of the
transmission of the nerve impulse
HR
HR
Skizze und Beschreibung der humoralen Übertragung
von Otto Loewi für seinen Sohn Guido, etwa 1950.
"If a nerve by a stimulus gets an impulse
this impulse is propagated within the nerve
and is transmitted to the respec tive effective
organs (heart, muscle, gland) innervated by
the nerve. The question arose by which means
the impulse coming from the nerve is transmitted
to the effector organ. I was able to solve this
question by proving that the impulse running
down within the nerve liberates from its endings
chemical substances (Acetylcholine or Adrenaline
respectively) which in their turn influence the
effector organ exactly like the stimulation of the
nerve. With other words: the influence of nervous
stimulation on an organ is not a direct one but an
indirect one mediated to the organ by chemical
substances released by the nerve stimulation in
its endings."
”the influence of nervous stimulation on an organ
is not a direct one but an indirect one mediated to
the organ by chemical substances released by the
nerve stimulation in its endings."
“So far as our present knowledge goes, we are led to
think that the tip of a twig of the arborescence is not
continuous with but merely in contact with the
substance of the dendrite or cell body on which it
impinges. Such a special connection of one nerve cell
with another might be called a synapse.”
(Sherrington, 1897)
The introduction of the functional term ”synapse”
{Synapse: ‘synaptein’ : Greek ‘syn-’ (together), ‘haptein’ (to clasp)}
Gray Type 2
asymmetrical synapse
(GABA)
Gray Type 2
symmetrical synapse
(glutamate)
S and F types
synaptic vesicles
(spheroid/flattened
(excitatory/inhibitory)
Types of synapses:
Chemical synapses: Electrical synapses
(gap junctions)
excitatory inhibitory depolarization
(presynaptic, hyperpolarization
postsynaptic
inhibition)
Figure 1 Electrical postsynaptic potentials in neurons from the mammalian brain.
Each case illustrates simultaneous intracellular recordings from a pair of similar neurons,
with presynaptic action potentials above and electrical postsynaptic potentials
below. (A) Two types of inhibitory interneurons from the neocortex: fast-spiking (FS)
cells and low threshold–spiking (LTS) cells. Traces are averaged from ten and eight
neuron pairs, respectively, and the dashed lines are ±SD (J.R. Gibson, M. Beierlein,
B.W. Connors, unpublished report). (B) Recordings from a pair of thalamic reticular
neurons in tonically spiking mode (left) and bursting mode (right). Action potentials
are truncated (from Long et al. 2004). (C) Inferior olivary neurons (MA Long, unpublished
report). (D) AII amacrine neurons from the retina (Veruki & Hartveit 2002a).
(E) Cerebellar interneurons (Mann-Metzer & Yarom 1999).
Electrical synapses (gap junctions)
GAP JUNCTION (~2 nm [20 Å])
HEMICHANNELS (CONNEXONS)
6 CONNEXIN SUBUNITS
4 TRANSMEMBRANE PROTEIN MOLECULES
Lack of synaptic delay
Low resistance
Shorter latency
Connexons direct the nerve impulse
in both directions
Dye-coupling
Electrical postsynaptic potentials in neurons
from the mammalian brain. Each case
illustrates simultaneous intracellular
recordings from a pair of similar neurons,
with presynaptic action potentials above and
electrical postsynaptic potentials below.
Electrical postsynaptic potentials in neurons
from the mammalian brain. Each case
illustrates simultaneous intracellular
recordings from a pair of similar neurons,
with presynaptic action potentials above and
electrical postsynaptic potentials below.
POSTSYNAPTIC POTENTIAL
PRESYNAPTIC ACTION POTENTIAL
CHEMICAL SYNAPSE
ELECTRICAL SYNAPSE
DYE COUPLING
LUCIFER
YELLOW
GAP JUNCTION
Connexin mutations
and human diseases:
About 20 connexins identified in the
human genom. Their mutations cause
inherited diseases.
Con32: Charcot-Marie-Tooth-disease
motor+sensory neuropathy
(muscular dystrophy)
Con26 & 30: deafness, skin diseases
Con46 & 50: hereditery cataract
Postsynaptic electrical events localized changes in membrane potential
EPSP: excitatory postsynaptic potential
depolarization:
increased Na+ and/or Ca++ influx
summation of EPSPs (temporal, spatial summation)
IPSP: inhibitory postsynaptic potential
hyperpolarization:
opening of Cl– channels – increased Cl– influx
or opening of K+ channels – K+ efflux
or closure of Na+ or Ca++ channels)
summation of IPSPs (temporal, spatial summation)
Inhibition and facilitation at synapses
Postsynaptic or direct inhibition (IPSP, glycine)
Presynaptic inhibition
axo-axonal synapses
- mostly mediated by a decrease in the Ca++ entry and
the consequent reduction in the release of the excitatory
transmitter
- K+ channels may be also opened
- direct inhibitory effect on transmitter release
- mediated by GABA
- result: selective elimination of specific inputs
Presynaptic facilitation
- increase of Ca++ entry and the consequent increase in the
release of the excitatory transmitter
- closing of K+ channels
Neurexin
(3 gén:1000 típus)
200-500 μs
Synaptic cleft:
20-40 nm
Presynaptic nerve
ending
Postsynaptic
neuron
action
potential receptor
Synaptic delay: 200-500 μs
T
T
T T
T
Synaptic vesicles
Transmitter (T)
~ 2000 Synapses/Nerve cell
1011 Neurons in CNS
Synapses in CNS ~ 2 x 1014
Neurexine
(3 genes:1000 types)
T
T
T T
T
axon
terminal dendrite
The classical chemical
synapse
Bipartite synapse
LICHTMANN & SANES, 2008 RETZIUS, 1893
NEUROGLIA - ASTROCYTA
SILVER IMREGNATION COMBINATORIAL EXPRESSION OF
GREEN, BLUE & RED
FLUORESCENT PROTEINS
BRAINBOW
THE TRIPARTITE SYNAPSE
PRESYNAPTIC AXON TERMINAL
POSTSYNAPTIC ELEMENT (DENDRITE) + ASTROCYTE
Ax
Ax
Astro
D
D
Halassa 2007
„Tripartite” szinapszis
-Glutamát reciklizálás - K+ „spatial buffering”- Gliotranszmitter ürítés
FUNCTIONS OF ASTROCYTES: Maintaining the functional integrity of neurons which are in direct physical contact with the astrocytes. Spatial potassium buffering in the extracellular (perisynaptic) space. Glutamate/glutamine recycling between neurons and astroglia. Release of gliotransmitters, modulation of synaptic transmission (ATP, glutamate, D-serine).
Quantal release of
neurotransmitters
Transmitter is
packaged in
vesicles and each
vesicle contains
approximately
10000 transmitter
molecules. Release
of transmitter from
a single vesicle
results in a quantal
synaptic potential.
QUANTAL MECHANISM OF NEURAL
TRANSMITTER RELEASE
TRANSMITTERSTranszmitter
kvantális felszabadulása
Near motor
endplate region
Remote endplate
region
SYNAPTIC VESICLE = 10000
Ach molecule: quantum
Sir Bernard Katz
KATZ: On our present evidence, the sequence of events may
be described as follows: depolarization opens specific
<calcium gates> in the-terminal axon membrane-this leads to
an influx of calcium ions… Having reached the internal
surface of the axon membrane, calcium ions then initiate the
"quanta1 release reaction". … a plausible and, I think, very
strong hypothesis, namely that the quanta of transmitter
molecules are enclosed within synaptic vesicles which
undergo frequent transient collisions with the axon
membrane, that calcium brings about attachment and local
fusion between vesicular and axon membranes, and that this
is followed by all-or-none discharge of the vesicular content
into the synaptic cleft.
MEP = miniature
endplate potentials [minis] (0.5-1 mV)
VESICULAR TRANSMITTER RELEASE
NATURE, 490:201(2012)
Transmitters are released through a calcium-dependent exocytosis
from synaptic vesicles after fusion with the presynaptic membrane
Synaptic vesicle cycle:
1. Docking in the active zone
2. Priming
3. Fusion, exocytosis
4. Endocytosis (clathrin)
5. Endosome fusion, recycling
6. Budding
7. Transmitter-uptake (proton pump)
8. Translocation into the active zone
vesicle
presynaptic axon terminal
Calcium imaging uses fluorescent dyes which change their spectral
characteristics after binding (ionic) calcium
[ ]
Synaptic vesicle docking proteins are
targets of neurotoxins (zinc endopeptidases)
Clostridium botulinum. Botulinum toxin A
(blepharospasm, strabismus, and
torticollis/cervical dystonia, wrinkles)
Tetanus: spastic paralysis by blocking
presynaptic transmitter release in CNS
Botulinismus: flaccid paralysis by
blocking Ach release at the NMJ
Proteins of the neuronal
fusion machine
TRANSMITTER
INACTIVATION
enzymatic elimination
inactivation through diffusion
COMT
AChE
ATP-diphosphohydrolase
(AMP 5’nukleotidase
adenosine)
RETROGRADE (ENDOCANNABINOID) SIGNALISATION
(INHIBITION OF TRANSMITTER RELEASE)
GIRK: G protein-coupled inwardly-rectifying
potassium channel ANA=anandamide,
2-AG=2-arachidonoylglycerol
Release of glutamate
Increase in postsynaptic
Ca2+ level
synthesis and (non-vesicular)
release of anandamide and
2-arachidonylglycerol
Activation of presynaptic
CB1 receptors
Release of Gβγ dimer
modulation of voltage
dependent CaV2
channel function
activation of GIRK:
presynaptic
hyperpolarization
Inhibition of transmitter
release
Acetylcholine (Ach)
Monoamines,
Catecholamines:
serotonin [5-HT]
histamine
dopamine
noradrenaline
adrenaline
Amino acids:
glutamate
aspartate
GABA
glycine
purines: ATP
PEPTIDES:
Tachykinins: GI peptides:
substance P secretin
neurokinin A glucagon
Opioid VIP
peptides: CCK
enkephalins somatostatin
endorphins bombesin
dinorphins gastrin
Neurohypophyseal Substance P
peptides:
vasopressin
oxytocin
Lipids: Others:
endocannabinoids CGRP, galanin
endovanilloids neurotensin,
NPY
gas: NO, CO
Dale’s principle: the same transmitter
agent is released from all axon terminals of the
neuron („one neuron, one transmitter”)
Colocalization of chemically different
transmitter agents
in peripheral and central neurons
Co-release of neurotransmitters from
peripheral and central neurons
Co-localisation
Co-release
of neurotransmitters
e.g. Ach--VIP
NA--NPY
TRH--5HT--SP
SP--CGRP(--GLU)
Note the frequency-dependence
of the release of the different
transmitter agents.
Neurotransmitter receptors – ion channels
Multiple receptors for most transmitters (adrenergic, cholinergic, etc.)
Postsynaptic and presynaptic receptors for many transmitters
Receptor families
Receptors (in clusters) are bound to the membrane by specific binding
proteins (rapsyn-NMJ, GABAA – gephyrin)
Desensitization: loss of responsiveness of the receptor to the ligand
(phosphorylation, increased endocytosis-receptor internalization)
direct
ligand gated
channels
Indirect ligand gated channels
Direct via G-Proteine
Indirect via
second
messengers
ionotropic metabotropic
IONOTROP AND METABOTROP RECEPTORS OF TRANSMITTERS
NEUROTRANSMITTER IONOTROP RECEPTORS METABOTROP RECEPTORS
Ach nicotinic Ach receptor muscarinic Ach receptor
5-HT 5-HT3 other 5-HT receptors
Glycine glycine receptor -
GABA GABAA & GABAC GABAB
Glutamate NMDA, AMPA, metabotrop glutamate r. KAINATE
ATP P2X P2Y
Dopamine - D1 receptor
Noradrenaline - α & β receptors
Histamine - H1 receptor
Glutamate receptors
AMPA: 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid
NMDA: N-Methyl-D-aspartate
LTP
Long-term potentiation
LTD
Long-term depression
Mechanisms of LTP and LDP may involve
phosphorylation and dephosphorylation of
synaptic proteins, respectively, regulated by
changes in intracellular calcium levels.
Superfamily of ligand-gated pentameric channels
Ach, 5-HT, GABA, Glycine
INCREASED FREQUENCY
OF CHANNEL OPENING INCREASED DURATION
OF CHANNEL OPENING
GABAA receptor channel
GOLGI (1891): ‘‘The structural contact or fusion between two nerve
fibers is not a necessary condition to have functional relationship
between different neurons ….. since, studies on electricity show that
electrical currents can link two conductors not in direct contact’’
This specific hypothesis has been subsequently demonstrated since
intercellular communication via electrotonic currents takes place in
the CNS. Furthermore, Golgi’s position may have an even broader
meaning, since, nowadays, most neuroscientists, in a more or less
explicit way, believe that there exists in the brain some kind of non-
synaptic, hormone-like, modulatory transmission besides synaptic
transmission.
Fuxe, Agnati (1991): wiring transmission WT and
volume transmission VT.
Paul Alfred Weiss Wien, March 21, 1898 — September 8, 1989
„outgrowth of neurons and their maintenance
depended on axonal flow from the nucleated
cell bodies in nerve centers”
„A pressure block (by suture, by passage into
a fibrotic zone such as a scar, or by other
means) caused piling up of the material of an
intact axon on the nuclear side and reduction
in diameter on the distal side of the
constriction.”
leucine-3H
Figure 5-10 Early experiments on axonal
transport used radioactive labeling of proteins.
In the experiment illustrated here the distribution
of radioactive proteins along the sciatic nerve
of the cat was measured at various times after
injection of [3H]-leucine into dorsal root ganglia
in the lumbar region of the spinal cord. In order to
show transport curves from various times (2,
4, 6, 8, and 10 hours after the injection) in one
figure, several ordinate scales (in logarithmic
units) are used. Large amounts of labeled protein
stay in the ganglion cell bodies but with
time protein moves out along axons in the sciatic
nerve and the advancing front of the
labeled proteins is displayed progressively farther
from the cell body (arrows). The velocity
of transport can be calculated from the distances
displayed at the various times. From
experiments of this kind, Sidney Ochs found that
the rate of axonal transport is constant at 410
mm per day at body temperature. (Adapted from
Ochs 1972.)
Intraneuronal transport of neuronal proteins
following the incorporation of [3H]-leucine
transport-velocity
410 mm/day
Axoplasmatic transport (Paul Weiss)
anterograde (somatofugal): trophic factors (Merkel, taste buds)
retrograd (somatopetal): Viruses, Toxins (Rabies; Tetanus),
[viral neuronal ”tracing”, transneuronal labelling of neural pathways]
Trophic factors (NGF, CNTF, BDNF, GDNF, etc)
Regulation of gene expression
Transport block (colchicin, Vinca-alkaloids; Depolimerization of microtubules)
Fast transport (e.g., transmitters) cm/day
Slow transport (e.g., cell organelles) mm/day
Dendritic transport