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Neurophysics Adrian Negrean - part 1 - [email protected].
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Transcript of Neurophysics Adrian Negrean - part 1 - [email protected].
![Page 2: Neurophysics Adrian Negrean - part 1 - adrian.negrean@cncr.vu.nl.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649cfa5503460f949cc367/html5/thumbnails/2.jpg)
Contents
1. Aim of this class
2. A first order approximation of neuronal biophysics
1. Introduction
2. Electro-chemical properties of neurons
3. Ion channels and the Action Potential
4. The Hodgkin-Huxley model
![Page 3: Neurophysics Adrian Negrean - part 1 - adrian.negrean@cncr.vu.nl.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649cfa5503460f949cc367/html5/thumbnails/3.jpg)
Introduction
(5)
(4)
(3)
(1)
(2)
1) Cell body
2) Axon
3) Apical dendrite
4) Basal dendrite
5) Synapses
histological staining of a single neuron in a rat brain (photo credits: Cristiaan de Kock, CNCR, VU, Amsterdam)
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Let’s watch a brief video clip for a quick check of what you (might) know about neurons:
http://www.youtube.com/watch?v=DF04XPBj5uc&feature=related
• Neurons connect to each other via synapses
• Fast communication (a few milliseconds) occurs through Action Potentials
• Action Potentials release neurotransmitters at the synapse
• Neurotransmitters bind to “special gates” on the other side of the synapse and let
in a “flood of charged particles” which start up a new electrical signal in the receiving
neuron
• A bunch of neurons forming intricate connections allows us to think imaginatively
Q: How is this possible ? physically speaking ?!
![Page 5: Neurophysics Adrian Negrean - part 1 - adrian.negrean@cncr.vu.nl.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649cfa5503460f949cc367/html5/thumbnails/5.jpg)
• There is a great diversity of neurons, and
people are still struggling to classify them
![Page 6: Neurophysics Adrian Negrean - part 1 - adrian.negrean@cncr.vu.nl.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649cfa5503460f949cc367/html5/thumbnails/6.jpg)
Electro-chemical properties of neurons
• Membrane capacitance
d
AC 0
“ parallel plate capacitor “
![Page 7: Neurophysics Adrian Negrean - part 1 - adrian.negrean@cncr.vu.nl.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649cfa5503460f949cc367/html5/thumbnails/7.jpg)
• Ion-channels:
1) Leak-channels
2) Voltage-gated ion-channels
3) Ligand-gated ion-channels
4) Metabotropic ion-channels Structure of a voltage-gated potassium selective ion-channel from the Kv1.2 gene
![Page 8: Neurophysics Adrian Negrean - part 1 - adrian.negrean@cncr.vu.nl.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649cfa5503460f949cc367/html5/thumbnails/8.jpg)
• Electrical circuit of a simple cell having:
1) Capacitance C
2) Leak ion-channels R
3) Membrane potential Vm
…keeping in mind that there are ions instead of electrons
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Na+
Na+
Na+
Cl-
Cl-
Cl-
A
Cl- permeablemembrane
water
E=0B
Na+
Na+
Na+
Cl-
Cl-
Cl-
E=ECl
• Ions and electrochemical potentials:
A) A Cl- semi-permeable membrane separates a salty solution from water
B) As time passes, Cl- diffuse, creating a potential difference
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in
oution ion
ion
zF
RTE
][
][ln
where z is the valence of the ion, R is the gas constant (8.315 J K-1mol-1), T is the temperature (K), F is Faraday’s constant (96.485 C mol-1) and [ion]o and [ion]i are the
concentrations of the ion inside and outside of the cell respectively
• Nernst’s equation for equilibrium potentials:
The membrane potential of a simple cell can be calculated using this
formula if the membrane is permeable only to one ion type.
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• Goldman-Hodgkin-Katz equation for equilibrium potentials:
(generalization of Nernst’s equation for membranes permeable to multiple ions simultaneously)
oCliNaiK
iCloNaoKm ClpNapKp
ClpNapKp
F
RTV ln
for example, the membrane relative permeability coefficients for the Squid Giant Axon are pK : pNa : pCl = 1.00 : 0.04 : 0.45 when the axon is at rest.
![Page 12: Neurophysics Adrian Negrean - part 1 - adrian.negrean@cncr.vu.nl.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649cfa5503460f949cc367/html5/thumbnails/12.jpg)
…so if you know the ion concentrations inside and outside the cell at rest
…and the relative permeability ratios
…then using the GHK equation you can calculate the resting membrane potential of the cell
but the simplest thing to do in practice is to just measure it
Intracellular and extracellular concentrations of different ions (millimoles) given in parentheses for a typical mammalian neuron and their Nernst
equilibrium potentials (mV).
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• Ion-channels:
- membrane-bound proteins
- conduct ions across the membrane
- are selective for certain ions
- they open/close in response to a wide range of stimuli:
a) electrical
b) mechanical
c) chemical
d) thermal
e) optical
f) intracellular
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• Ion-channel gating is a stochastic process
C: Gramicidin A peptide has been added to a
phospholipid bilayer membrane to form trans-
membrane channels that allow passage of ions.
A: The formation of functional Gramicidin A
channels can be seen as random step-increases
in current when a potential difference is applied
to the membrane. B: The size of the current
steps is related to the applied potential through
Ohm’s law.
example: an Ohmic leak channel
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• when describing Ohmic single channel leak currents, the reversal potential has to be also taken into account:
revLL EEgI
single channel conductance
single channel current
membrane potential
reversal potential for the ions involved
• for the great majority of ion-channels, the single channel conductance is not constant but depends on the membrane potential
voltage-gated ion-channels
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Q: So what are voltage-gated ion-channels good for ?
A: Action Potentials, among other many interesting examples
The nerve impulsewatch video:
An Action Potential propagates down the axon, and causes the release of a neurotransmitter at the synaptic cleft
watch video: Synaptic transmission
Finally the released neurotransmitter binds to ion-channels in the post-synaptic neuron, and depolarizes the cell.
Action Potential propagationwatch video:
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Let’s have a closer look at what the ion-channels do during an Action Potential:
Ion-Channels involved in the Action Potentialwatch video:
main points:
1) Voltage-gated ion-channels have gates
2) These gates open/close with different
speeds
3) The opening / closing of ion-channels is
actually a change in the coformational state of
the protein
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• Single-channel kinetics involved in AP production
K+ channels
- the opening of the channel requires 4 independent subunits to change conformation
kK nP
probability of a subunit to change conformation
k=4
probability for channel to be open
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- the subunit open probability n is related to the membrane potential through a first order kinetic scheme
closed / open subunit conformation
voltage-dependenttransition rates
- in practice the voltage-dependent transition rates are fitted to measured data, still in this case, thermodynamic arguments give a good result
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here’s the thermodynamic argument:
1) the subunit contains a charged domain q that couples to the
transmembrane electric field E=V/d
2) a movement of the subunit means that a fraction Bα from the charge
q moved within the electric field E doing a work of q BαV
3) Boltzmann statistics says that the probability to make a transition to
a state of higher energy, qBαV is proportional to:
)/exp( TkVqB B temperature
Boltzmann’s constant
energy separating the two states
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thus )/exp()( TkVqBAV Bn
(in Chemistry this kind of equation is known as
Arrhenius’s law describing reaction rates)
- a similar equation can be written also for the reverse transition rate
Na+ channels
hmP kNa
k=3
- in addition to three activation subunits m they also have an inactivation
subunit h that closes the channel after a while, even if the activation subunits
are open
- same thermodynamic arguments as for the K+ channels
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The Hodgkin-Huxley model of AP’s
- describes the phenomenon of Action Potential generation in neurons
- the model was applied to the Squid Giant Axon and later generalized to
other neurons
(1)
(2)
(3)
(4)
(5)time
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LNaK I
LL
I
NaNa
I
KKinj EVgEVhmgEVngIVC )()()( 34
using Kirchhoff’s laws:
(the dot is a time derivative)
capacitor current
![Page 24: Neurophysics Adrian Negrean - part 1 - adrian.negrean@cncr.vu.nl.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649cfa5503460f949cc367/html5/thumbnails/24.jpg)
- now we have to add the single-channel gating kinetics for both Na+ and K+ as described before:
nVnVn nn )()1)((
mVmVm mm )()1)((
hVhVh hh )()1)((
110
10exp
1001.0)(
VV
Vn
80
exp125.0)(V
Vn
110
25exp
251.0)(
VV
Vm
18exp4)(
VVm
20
exp07.0)(V
Vh
110
30exp
1)(
V
Vh
- and specify also the channel conductances and reversal potentials
![Page 25: Neurophysics Adrian Negrean - part 1 - adrian.negrean@cncr.vu.nl.](https://reader035.fdocuments.net/reader035/viewer/2022062515/56649cfa5503460f949cc367/html5/thumbnails/25.jpg)
and the result is: