Download Ca 2+

E. Neher
Brainsignals, Synaptic Transmission and
Short-term Plasticity
.... and about Young Investigator Groups in Europe
Ideas of the ERC and Excellence in Research
Tallinn
May 29th, 2007
The Origin of ‚Bioelectricity‘:
1780 - 1800
Galvani
Volta
Lichtenberg
Ramon y Cajal
1904
First, second and third layer
of the cerebrum of a child
of 1 month age
Our brain is a network of
1012 neurons, each of
which is connected with
thousands of other cells
by synapses
Ramon y Cajal already predicted the direction
of signal propagation
- and was mostly right -
Each neuron receives input at
its dendrites from thousands
of other neurons
Dendrite
These signals are being
integrated (added up) and a
new nerve impulse is
generated, when a certain
threshold is surpassed.
Cell Body
Axon
Brain:
- 100 000 000 000 nerve cells
- 1 000 000 000 000 000 connections
- 1000 computational cycles per sec
Computer:
- 1 000 000 transistors
- 1 000 000 000 cycles per second
Moore‘s Law:
The number of transistors, which can
be packed onto a chip, doubles every
18 months
----> the number of transistors in a
computer could reach the number of
brain nerve cells in 25 years
Important Difference:
The connections within the brain are
‚plastic‘
Information processing in the brain is
highly parallel
Dendrite
Cell Body
Axon
Synaptic Plasticity
•
•
•
•
•
Neuroscientists use the term ‚Plasticity‘ to
describe the observation that synaptic
strength changes constantly, depending
upon use of a synapse
Plasticity of synaptic connections underlies
the complex information processing of the
CNS
Plasticity occurs on time scales of
milliseconds to years
Nature uses all possible mechanisms, to
achieve a finely tuned regulation of
synaptic transmission
When we study synaptic transmission
today, we not only want to understand the
process of transmission per se, but also
why synaptic strength changes in a usedependent manner
Short Term Plasticity is specific for individual synapses and
may be different for two branches of the same axon
Short term depression is a key mechanism for a number of
network properties
•Sensory Adaptation (Chung et al., 2002. Neuron 34, 437-446)
•Cortical Gain Control (Abbott et al.,1997. Science 275, 220-224)
•Rhythm Generation (Senn et al., 1996. Neural Networks 9 ,575-588)
•Network Resonance (Houweling et al., 2002. J. Physiol 542, 599-617)
•Temporal Filtering (Fortune and Rose, 2001. TINS 24, 381-385)
Synaptic Transmission
Short term plastic changes may
have many causes:
• Presynaptic
- action potential waveform
- modulation of Ca++-currents
- Ca++ buffers
- Depletion of release-ready
vesicles
• Postsynaptic
- Desensitization
- Block by Polycations
In general, presynaptic terminals are very small,
such that the study of neurotransmitter release is
difficult
....However, it has been
known for more than 100
years, that there are giant
nerve terminals in certain
regions of the brain
Cajal: ‚Calices de Held,
para refutar antineuronistas‘
The calyx of Held synapse
in the auditory brainstem pathway
B
A
C
Calyx pioneers: Hans Held (1893) Arch. Anat. u. Physiol 17, 201 - 248
Ian D. Forsythe (1994) J. Physiol 479,381 -387
Gerard J. Borst et al. (1995) J. Physiol 489,825 -840
....the postsynaptic current
elicited by afferent nerve
stimulation
Synaptic depresssion and facilitation can be
expressed at the same synapse
(reponses to 100Hz trains of stimuli)
2 mM Ca
2+
4 nA
0.5 mM Ca
2+
1 nA
5 ms
...both pre- and postsynaptic changes contribute to depression
Presynaptic parameters influencing short-term plasticity
Local intracellular
Calcium concentration
p(Ca)
Readily-releasable
pool
of vesicles, N
ICa
What is the microdomain [Ca2+] needed for
presynaptic vesicle fusion?
p (Ca)
ICa
Transmitter release evoked by presynaptic
Ca2+ uncaging
Conclusions I
• Ca++ uncaging allows one to establish a ‚dose-response-curve‘
- release-rate versus [Ca2+] • During an action potential [Ca2+] is postulated to rise to a
peak of ≈ 20µM and 0.5msec width at the release site
• Such high Ca++ concentrations are only obtained in
microdomains around open Ca++ channels, which rapidly
collapse, when channels close.
...
recent measurements by Bollmann and
Sakmann Nat Neurosci. (2005), 8, 426-34, in which short [Ca2+]
-transients were produced by uncaging, show that only
such short transients produce responses, which are
similar to action potential-induced ones
Facilitation: Proposed Mechanisms
•Residual Calcium (Katz and Miledi)
•Extra Calcium Senor
•Unblock of Polycations (postsynaptic)
Question:
Does Ca++ sensitivity change during pairedpulse facilitation
A form of synaptic facilitation downstream of Ca2+ entry
studied by presynaptic voltage clamp
Next: Replace this test pulse by a flash
A
B
Is the Ca2+ sensitivity of vesicle fusion increased
during synaptic facilitation?
Δ[Ca]i
Unchanged relation between transmitter release and
intracellular Ca2+ during synaptic facilitation
A
B
.....short term facilitation is not an increase in the sensitivity of the release apparatus,
but rather an increase in the effectiveness of Ca++ influx.
Conclusions from Ca++ uncaging :
• Ca++ uncaging allows to establish a ‚dose-response-curve‘
- release-rate versus [Ca2+]
• during an action potential [Ca2+] rises to a peak of ≈ 20uM
• the Ca++ sensitivity of the release apparatus does not change
during short term facilitation
‚Top-Down‘ and ‚Bottom-Up‘ Approach to
Neuroscience
ENI-Net:
A European network, dedicated to the
promotion of Young Investigators
Its Goals:
• Promote the independent research of Young
Investigators (Career Development)
• Intensify Collaboration and trainig
• Stimulate Joint Activities, including applications to
other programmes of the EU
• Contribute to the establishment of the ‘European
Research Area’
ENI-Net:
A European network
- the Alicante Meeting January, 2004
The participating Institutions commit
themselves to provide laboratory space and
infrastructure for at least 2 Young Investigator
Groups
Independence of Young Investigators is
monitored by a ‘Steering committee’
Plans for:
Yearly meetings, workshops, and exchange
stimulating intensive collaboration
Steering Committee of ENI-Net:
Dr. David Attwell, London
Dr. Carlos Belmonte, Alicante
Dr. Christoph Mulle, Bordeaux
Dr. Erwin Neher, Göttingen (Chair)
Dr. Eva Sykova, Prague
ENI-Net:
A European network, dedicated to the
promotion of Young Investigators
Application to Brussels for a Coordination Action in
the Neurosciences (Sep. to Nov. 2004) :
Twelve Institutes in 2004, now 18
48 Young Investigators approved by the Steering Committee
1.2 Mio € granted through a CA for yearly meetings, workshops, and
exchange
......as of
Dec, 2006
2007:
Waiting for
ERC-groups
to join