Transcript Maths in Medical Science

Extracellular Environment
of CNS Neurons & Glia
Tony Gardner-Medwin,
Physiology room 331
[email protected]
www.ucl.ac.uk/lapt/med
Please use the Web Discussion Forum
for problems/queries
CNS Extracellular Environment
Is there any e-c space?
- size, composition
The macro-environment: CSF, blood
Homeostasis, Disturbances
- (normal, pathological)
Role of glia in K+ homeostasis
Failures of regulation:
The war between + feedback and - feedback
From Neuron to Brain (Nicholls, Martin & Wallace)
- Chapter on Neuroglia
Is there any extracellular space?
Photoreceptors (dark)
and glial cells in the
compound bee eye
Neurons & glia (shaded) in mammalian cerebellum
Measurement of Extracellular Space Volume
1. 15-20nm gaps => 2% - 5%
but ? are cells swollen to occlude space?
2. Try e-c markers from blood: don’t show up ( ‘Blood-Brain Barrier’ )
? Is this lack of penetration due to zero e-c space?
3. Markers from CSF: 10-20% space, but v slow equilibration
4. Improved EM technique: rapid freezing -> 18 - 25%
EM after rapid freezing, <30s after cessation of circulation
EM after rapid freezing, 8 min after cessation of circulation
Measurement of Extracellular Space Volume
1. 15-20nm gaps => 2% - 5%
but ? are cells swollen to occlude space?
2. Try e-c markers from blood: don’t show up: ‘blood-brain barrier’
? Is the lack of penetration due to zero e-c space?
3. Markers from CSF: 10-20% space, but v slow equilibration
4. Improved EM technique: rapid freezing -> 18 - 25%
5. Release of e-c markers from electrodes, and measurement
of concentration, with ion-selective electrodes -> 15 - 25%
Measurement of Extracellular Space Volume
Five methods ……
Conclusions
~ 20% e-c space (similar to rest of body)
Cut off from blood (unlike elsewhere)
Free (but slow) diffusion exchange with CSF
….. but what about its composition?
Functions:
Mechanical: floating brain
↓ postural effects
lubrication / movement
pressure ≈ venous (10 mmHg)
Variable volume reservoir
(but only a few % of brain volume)
Clearance (like lymph)
Homeostasis:
regulated composition
How successful is K+ homeostasis?
Plasma [K+]
CSF [K+]
Normal Diet:
4.2
2.8
mM
Low K diet:
1.6
2.7
mM
High K diet:
7.1
3.0
mM
Baseline e-c [K+]o measured with ion-selective micro-electrodes is
similar to CSF (normally less than plasma, and well regulated)
Does neural activity alter e-c [K+] ?
Epileptic discharges in cortex -> transient increase
of extracellular [K+] and depolarisation of astrocytes
Leech ganglion, showing neurons and glia
Electrical properties of glial cells
Initially studied in leech n.s.
1. Large resting potentials ( ~ -90 mV cf neurons -70 mV)
2. Inexcitable (no action potentials)
3. Electrically coupled (via GAP junctions)
4. Vm sensitive to [K+]o - follows Veq(K+)
- membranes very selectively permeable to K+
5. Slow, long depolarisations when adjacent neurons are
stimulated
6. Can take up K+, GABA, glutamate from e-c space
Effect of light stimulation on K+-selective electrode
concentration measurements in bee eye
[K+]i
(mM)
[K+]i
[K+]o
Effect of visual
stimulation with
moving bars of light,
on glial Vm in cat
visual cortex
-60
Glial membrane
potential (mV)
-72
0
10
20
30
40
50 s
K+ ‘spatial buffer’ mechanism disperses potassium from regions of
activity & build-up, into normal tissue and to surface fluid
Diagrammatic
version of the
coupled astrocyte
network
REGULATION OF E-C [K+]
1. EXCHANGE WITH BLOOD: SLOW !!
Accurate homeostasis but only regulation of average
concentration over many hours
2. DIFFUSION :
Evens out local disturbances, reducing their maximum effect.
Effective only over short distances, and would be BETTER
without the blood-brain barrier.
3. GLIAL UPTAKE and DISPERSAL via SPATIAL BUFFER
mechanism. Assists dispersal by diffusion ( ~ 5x) Helps to
reduce disturbances due to neural activity.
But why is regulation important ??
Wave of drastic, but
transient disturbance of
extra-cellular K+ and
Ca++ concentrations
spreading from local
trauma in baboon cortex
‘Cortical Spreading
Depression’
(probably part of the
syndrome in migraine
and stroke)
Positive feedback may lead to e-c instability in
stroke, migraine and trauma
Raised [K+]o
- feedback
Depolarisation
GLIA
+ feedback
NEURONS
Spatial Buffer currents
Transmitter Release
K+ uptake and
dispersal
Raised PNa, PK, PCl
K+ release
The End