Neuronal plasticity

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Neuronal plasticity

• The efficacy of synaptic transmission in the
  brain is activity-dependent and continuously
  modified. Examples of such persistent
  modification is long-term potentiation and
  depression (LTP and LTD).
• LTP/LTD is an increase/decrease in synaptic
  efficacy, which can be elicited by the
  conjunction of pre- and postsynaptic activity.
• LTP and LTD not only are of physiological
  importance, but might also play major roles in
  various pathological events.

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Neuronal plasticity

• The establishment and modification of neural
  networks are vital for normal brain functioning.
  These neural networks include both excitatory and
  inhibitory synaptic transmission.
• LTP, the long lasting enhancement of synaptic
  transmission , has long been regarded, along with
  it's counterpart LTD, as a potential mechanism
  for memory formation and learning.

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LTP -induced changes can last for many days

• Population spike

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LTP induced by tetanic stimulation
A. A weak test pulse (left) evokes the
postsynaptic response sketched on the right-hand
side of the figure. B. A strong stimulation
sequence (left) triggers postsynaptic firing
(right, the peak of the action potential is out
of bounds). C. A test pulse applied some time
later evokes a larger postsynaptic response
(right solid line) than the initial response.
The dashed line is a copy of the initial response
in A (schematic figure).

• after

• before

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Homosynaptic LTP

• tetanized

LTP is pathway specific. Only one pathway
(stimulus I) was tetanized. Pathway II remained
unaltered.

• Stimulus I

• Stimulus II

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Associative (cooperative) LTP
Two week inputs tetanized individually do not
produce LTP (I and II tetanus). When the two
inputs are co-activatedm (III), their
cooperative action triggers LTP.
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Calcium as a signal

• The NMDA receptor is blocked by a Mg ion at
  resting potential

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Transmission between individual neurons is
highly variable. Fluctuations in synaptic
responses recorded intracellular from a pyramidal
cell by one or few afferents. Note that responses
occur in what appears to be discrete steps. After
LTP the EPSCs increased. Quantal analysis of of
unitary responses indicates larger postsynaptic
responses.
LTP results in a change in quantal content
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Backpropagation of Na spikes from soma to
dendrites
Kamondi et al J Neurosci 1998
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Spike-timing-dependent synaptic plasticity
Timing requirements between pre- and postsynaptic
spikes. Synaptic changes occur only if
presynaptic firing at and postsynaptic activity
occur sufficiently close to each other. A
positive change (LTP) occurs if the presynaptic
spike precedes the postsynaptic one for a
reversed timing, LTD occurs.
Markram et al., 1997 Bi and Poo, 1998
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• Hypothetical steps in LTP
• Elevation of Ca in the postsynaptic spines
  (e.g. through NMDA channels)
• CaMKII autophosphorilation
• cAMP-dependent protein kinase (PKA)
• Insertion of AMPA receptors
• Division of synapses

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A hypothetical molecular cascade
Malenka and Nicoll, 1999
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(A) EPSP slope LTP in the dentate gyrus in vivo
recorded during chronic minipump infusion of
artificial cerebrospinal fluid (aCSF) or 30 mM
D-2-aminophosphonopentanoic acid (D-AP5) to block
NMDA receptors. Superimposed waveforms from each
group are shown before the tetanus (solid lines)
and 37 min afterward (dotted lines). LTP was
completely blocked by AP5 infusion (SJ Martin).
(B) LTD in area CA1 in vivo. Low-frequency
stimulation (l.f.s.) consisted either of 200
pairs of pulses delivered at 0.5 Hz with a 25-ms
interstimulus interval or 400 pulses at 1 Hz.
Only the former protocol induced robust LTD.
Thiels et al (1994). Sample waveforms are
illustrated as described in A. (C) The reversal
of dentate LTP by l.f.s. in vivo. Rats received
either a tetanus only or a tetanus followed 2 min
later by a 10-min period of 5-Hz stimulation.
Note that posttetanic stimulation was equivalent
in both groups prior to l.f.s. Martin Morris
(1997).
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Various methods for inducing LTD or depotentiation
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Working hypothesis for the activation of
heterosynaptic LTD. Activation of NMDAR leads to
a calcium influx and monosynaptic LTD. Coincident
activation of both NMDAR and mGluR leads to a
calcium influx AND the production of IP3. Both of
these signaling systems act on calcium stores in
the spine head to induce a release of calcium
from intracellular stores. In the absence of PI3K
and PKC activity, this calcium release in
combination with overproduction of IP3 also leads
to the release of calcium from dendritic calcium
stores. This leads to a wave of calcium-induced
calcium release (via the ryanodine receptor) that
ultimately results in a calcium release in
neighboring synapses and coincident LTD. IG
Collingridge)
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• Key references
• Bliss, T. V. P. and Lomo, T. (1973).
• Long-lasting potentation of synaptic transmission
  in the dendate area of anaesthetized rabbit
  following stimulation of the perforant path. J.
  Physiol., 232551-356.
• Collingridge, G. L., Kehl, S. J., and McLennan,
  H. (1983).
• Excitatory amino acids in synaptic transmission
  in the schaffer collateral-commissural pathway of
  the rat hippocampus.
• J. Physiol., 33433-46.
• Gustafsson, B., Wigstrom, H., Abraham, W. C., and
  Huang, Y.-Y. (1987).
• Long-term potentiation in the hippocampus using
  depolarizing current pulses as the conditioning
  stimulus.
• Hessler, N. A., Shirke, A. M., and Malinow, R.
  (1993).
• The probability of transmitter release at a
  mammalian central synapse.
• Nature, 366569-572.

There are many more papers on LTP and LTD than
the number of seminars you attend in your entire
life. This web site lists some of
them http//homepages.nyu.edu/eh597/ltp.htm
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Kindling, a laboratory model of certain epileptic
seizures, is another plasticity phenomenon. The
essence of kindling is the "Afterdischarge"
(shown below). Daily repetition of an
afterdischarge will spread to larger and larger
areas of the brain. Once motor structures are
involved, it can result in tonic-clonic muscular
activity. Although the evoking conditions of
kindling, LTP and LTD are similar the outcome is
very different. Unless stimulation evokes an
afterdischarge, no amount of LTP train repetition
will lead to kindled seizures. Thus, the
physiological, molecular changes underlying
kindling must be brought about by the
afterdischarge rather than by the stimulation.
(Goddard, 1967)
Hargreaves, E.L
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Inhibitory shunting of dendritic excitation
K. Harris
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Growth of dendritic spines (arrows) in response
to synaptic stimulation in a brain slice. The
neuron was filled with enhanced GFP by viral
transfection and imaged with two-photon laser
scanning microscopy. (from K. Svoboda).
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Enriched environment results in more numerous and
large spines of pyramidal cells, indicative of
more synapses
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Synaptic plasticity may underlie several human
diseases
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Exposure to novel environment abolishes LTP
a, High-frequency (200 Hz, arrow) stimulation
induced stable LTP when induced and recorded in a
familiar environment (FE). The amplitude of the
field excitatory postsynaptic potential (EPSP)
was significantly increased. b, c, LTP was
rapidly reversed when the animal was placed in a
novel environment 1 h after the application of
the high-frequency stimulation. Although the EPSP
amplitude was increased at 1 h on introduction to
the new environment (NE) synaptic responses
returned towards baseline values. LTP was still
absent 24 h later when recorded in the familiar
environment (98.5 1.7). b, Example of a
two-pathway experiment. Test (black circles and
lower traces) versus ipsilateral non-tetanized
control pathway (white triangles and upper
traces). Horizontal bar, 10 ms vertical bar,
2 mV. d, Handling the animals by removing them
from the familiar box to their home cage 1 h
after inducing LTP had no significant effect on
the magnitude of LTP when measured 24 h later in
the familiar box.