Transcript Document

•Now we know how synapses work
•Next:
- integration of synaptic excitation and inhibition
- synaptic plasticity
- diseases of neuromuscular transmission
1
Integration
•Each central neurone has thousands of excitatory and
inhibitory inputs
•How does it “decide” whether to fire an AP?
•It depends on whether the axon hillock is sufficiently
depolarised to reach threshold
•Now we’ll look at what determines potential at the axon
hillock
2
Synaptic integration
•Recording EPSP and IPSP
•This tells us potential at the soma
•Let’s see how the EPSPs and IPSPs interact
3
Temporal and spatial summation
•This shows only
EPSPs
•Of course some
of these potentials
will be IPSPs
4
Summation of EPSPs and IPSPs
•“Naive summation” model
•This is part of the story but oversimplified
•...the reality is more complex
•Let’s look at the importance of synapse position
5
Potential at
synapse and
soma
•Graded potentials
fall off quickly with
distance
•EPSP at soma
can be as little as
10% of that at
synapse
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Potential at
synapse and
soma
•Voltage falls
exponentially with
distance
•Just like local circuit
currents
•Falling off with
distance is described
by the SPACE
CONSTANT
•(see extra material
online – lecture 5)
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The space constant
•Plotting amplitude against distance from block:
1
0.8
Fraction of
original
amplitude
0.6
1 space constant
0.4
0.2
~37% of original
amplitude
0
•After 1 space constant, voltage declines to 1/e of its
original value (about 37 %)
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Space constant of a neurone
Potential at
synapse and
soma
•Graded potentials
fall off quickly with
distance
•EPSP at soma
can be as little as
10% of that at
synapse
•How fast potential
falls off depends
on the space
constant
•So in this situation...
•What matters is how many
space constants separate
the synapse from the soma
•This determines what
fraction of the EPSP gets to
the soma (thus the axon
hillock)
•This can be expressed as
the “electrical distance” of
the synapse from the soma
9
Where the synapses are
Type I (excitatory)
Type II (inhibitory)
...why does that matter?
10
How the IPSP inhibits
ECl = Er
ECl < Er
•Inhibitory synapses are between the excitatory synapses and the axon hillock
•Current from the EPSP has to pass them on the way to the axon hillock
•Regardless whether the IPSP is hyperpolarising or zero it still “shunts” current
from the EPSP
•This (and not the hyperpolarisation) is what makes an IPSP inhibitory
11
Summary of synaptic integration
•Position: excitatory synapses are situated mainly on dendrites,
inhibitory synapses on the soma
•How much of the synaptic current reaches the axon hillock
depends on electrical distance of the synapse from the soma
•EPSPs sum in space and in time (temporal and spatial
summation) to produce a total soma depolarisation
•...but this depolarisation is “captured” by inhibitory synapses lying
in wait on the soma, between the excitatory synapses and the
axon hillock
•A proportion of the depolarising current from the EPSPs is “shortcircuited” by the inhibitory synapses
•Only the remainder is able to depolarise the axon hillock
12
Myasthenia gravis
•Affects 50-125 people per million
•Causes weakness which gets worse as the patient
makes more effort - weakness varies from day to day
•Affects posture, walking and facial muscles
Untreated MG
Treated (same person)
13
Myasthenia gravis
•What causes it?
•Disease of neuromuscular transmission:
- Dale et al: ACh is the transmitter at the neuromuscular
junction
- Mary Walker (1934): based on Dale’s work, showed
that acetylcholinesterase inhibitors improve myasthenia
gravis
14
Myasthenia gravis: an autoimmune disease
Evidence:
•MG often accompanies thymus tumour
•...and often accompanies other autoimmune diseases
•It may be improved by removing the thymus
•Finally: antibodies against ACh receptor are found in
patients with MG
•Inject ACh receptor into mice: they make antibodies
and get MG
After neostigmine
15
Myasthenia gravis
Reduced density of ACh receptors in MG:
Normal
MG
16
Myasthenia gravis
Reduced density of ACh receptors in MG:
while nerve terminal is normal
Normal
MG
...why does this happen? 17
Myasthenia gravis: MEPPs
•Miniature endplate currents at NMJ of myasthenic
muscle are smaller than normal
•Suggests reduced ACh sensitivity at endplate
2 ms
18
Endplate potential is reduced in MG:
like the effect of curare
Curare
AP
Endplate potential
(EPP)
19
Endplate potential is reduced in MG:
like the effect of curare
•Curare reduces the EPP amplitude so that it is
sometimes subthreshold
•MG does the same
AP
Endplate potential
(EPP)
20
Effect of reduced EPP in MG
Transmission failure: reduced number of
muscle fibres active
21
Result: muscle action potentials decline
•If we stimulate motor nerve repetitively and record from
muscle in MG this is what happens:
... APs decline because
EPPs in some fibres are
subthreshold
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Reading for today’s lecture:
•Purves et al chapter 5 (pages 101 - 107); chapter 8 (pages 169-177);
box 6B (page 117)
•Nicholls et al chapter 12 (pages 232-238); chapter 22 (pages 449-452)
•Kandel et al chapter 12, chapter 63 (pages 1259-1272), chapter 16
Next two lectures:
Somatosensory system: mechanosensation, temperature and pain
•Purves et al chapter 9 (give particular emphasis to the part up to page
198, but please read the rest of the chapter too); chapter 10 (all)
•Nicholls et al chapter 17 pages 334-340 - see also chapter 18 pages
356-362
•Kandel et al chapters 21-24
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