Transcript Aplysia

Molecular Mechanisms of
Learning and Memory
Ying Shen, Ph.D.
Voice: 0571-88208240 Email: [email protected]
Department of Neurobiology
Zhejiang University School of Medicine
Plasticity Is Hot!
Eric R. Kandel
Aplysia Californica
Why Aplysia ?
Cellular Mechanism of Habituation
Cellular Mechanism of Sensitization
Hebbian Hypothesis
A neurophysiological postulate:
When an axon of cell A is near enough
to excite a cell B and repeatedly or
persistently takes part in firing it, some
growth process or metabolic change takes
place in one or both cells such that A's
efficiency, as one of the cells firing B,
is increased.
Hebb: The Organization of Behavior, 1949.
Donald Hebb
A Model For Hebbian Theory
where Xj and Yt are presynaptic and
postsynaptic activities, respectively,
and e > 0 is learning rate.
Long-Term Plasticity in Hippocampus
Bliss and Hippocampal LTP
Population
spike
LTP -induced changes
can last for many days
Long-Term Potentiation in Hippocampus
A. Experimental setup for demonstrating LTP in the hippocampus.
The Schaffer collateral pathway
is stimulated to cause a response
in pyramidal cells of CA1.
B. Comparison of EPSP size in
early and late LTP with the early
phase evoked by a single train
and the late phase by 4 trains
of pulses.
LTP Is Homosynaptic
Stimulus I
LTP is pathway specific. Only one
pathway (stimulus I) was tetanized.
Pathway II remained unaltered.
Stimulus II
LTP Is Associative (cooperative)
Two week inputs tetanized
individually do not produce LTP
(I and II tetanus). When the two
inputs are co-activatedm (I+II),
their cooperative action triggers
LTP.
LTP results in a change in quantal content
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.
Hypothetical Steps in LTP
•Elevation of Ca++ in the postsynaptic spines (e.g. through
NMDA channels)
•CaMKII autophosphorilation
•cAMP-dependent protein kinase
•Insertion of AMPA receptors
•Division of synapses
Normal Synaptic Transmission
During normal low-frequency trans-mission, glutamate interacts with NMDA and
non-NMDA (AMPA) and metabotropic receptors.
Induction of Long-Term Potentiation
With high-frequency stimulation other events occur as described in the text
Expression of Long-Term Potentiation
Filopodia
Dendritic Spines Growth
Growth of dendritic spines 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.
Water Maze Learning
Properties of LTP
Cooperativity
The probability of inducing LTP increases with the number of
stimulated afferents and the strength of stimulation, which reflects the
postsynaptic depolarization threshold that must be exceeded in order to
induce LTP. The voltage dependency of the NMDA receptor establishes
this threshold.
Input specificity
LTP is restricted to the synapses that triggered the process and does
not propagate to nearby synapses.
Associativity
Weak stimulation of one pathway may be insufficient to induce LTP,
though when coupled with strong stimulation of another, LTP can be
induced in both pathways.
Different Plasticities In Hippocampus
(A) EPSP slope LTP in the dentate gyrus in vivo
recorded during chronic minipump infusion of
artificial cerebrospinal fluid (aCSF) or 30 mM
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.
(B) LTD in area CA1 in vivo. Low-frequency
stimulation 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.
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.
Induction Mechansim For Hippocampal LTD
Long-Term Plasticity in Cerebellum
Cerebellar Structure
Whole-cell recording in Purkinej cells and LTD
200 pA
20ms
Induction of Cerebellar LTD
A Model For Cerebellar LTD
Cerebellar LTD in Eye Blink Conditioning
Various Methods for Inducing LTD or Depotentiation
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.

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.
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., 232:551-356.
•Collingridge, G. L., Kehl, S. J., and McLennan, H. (1983).
Excitatory amino acids in synaptic transmission in the schaffer collateralcommissural pathway of the rat hippocampus.
J. Physiol., 334:33-46.
•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. J. Neurosci.
•Hessler, N. A., Shirke, A. M., and Malinow, R. (1993).
The probability of transmitter release at a mammalian central synapse.
Nature, 366:569-572.
Thank you
School of Medicine, B515