•Now we know how synapses work

•Next:- integration of synaptic excitation and inhibition- synaptic plasticity- diseases of neuromuscular transmission

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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

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Synaptic integration

•Recording EPSP and IPSP•This tells us potential at the soma•Let’s see how the EPSPs and IPSPs interact

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Temporal and spatial summation

•This shows only EPSPs•Of course some of these potentials will be IPSPs

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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

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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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•Plotting amplitude against distance from block:

•After 1 space constant, voltage declines to 1/e of its original value (about 37 %)

The space constant

1 space constant

1

0.8

0.6

0.4

0.2

0

Fraction of original

amplitude~37% of original

amplitude

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Space constant of a neurone

•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

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

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Where the synapses are

Type I (excitatory)

Type II (inhibitory)

...why does that matter?10

How the IPSP inhibits

•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

ECl = Er

ECl < Er

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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 “short-circuited” 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

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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

Normal

MG

Reduced density of ACh receptors in MG:

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Myasthenia gravisReduced 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

Endplate potential (EPP)

AP

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•Curare reduces the EPP amplitude so that it is sometimes subthreshold

•MG does the same

Endplate potential (EPP)

AP

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Endplate potential is reduced in MG:like the effect of curare

Effect of reduced EPP in MG

Transmission failure: reduced number of muscle fibres active

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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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