Molecular Mechanisms of LearMolecular Mechanisms of Learning and Memoryning and Memory

Ying Shen, Ph.D.Ying Shen, Ph.D.Voice: 0571-88208240 Email: yshen@zju.edu.cnVoice: 0571-88208240 Email: yshen@zju.edu.cn

Department of NeurobiologyDepartment of NeurobiologyZhejiang University School of MedicineZhejiang University School of Medicine

Plasticity Is Hot!

Eric R. Kandel Aplysia CalifornicaCalifornica

Why Aplysia ? ?

Cellular Mechanism of Habituation

Cellular Mechanism of Sensitization

Donald Hebb

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.

A Model For Hebbian Theory

where Xj and Yt are presynaptic and postsynaptic activities, respectively, and > 0 is learning rate.

Long-Term Plasticity in HippocampusLong-Term Plasticity in Hippocampus

Bliss and Hippocampal LTP

LTP -induced changes can last for many days

Population spike

A. Experimental setup for demon-strating 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.

Long-Term Potentiation in Hippocampus

LTP Is Homosynaptic

Stimulus I

Stimulus II

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

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.

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

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 TransmissionNormal Synaptic Transmission

During normal low-frequency trans-mission, glutamate interacts with NMDA and non-NMDA (AMPA) and metabotropic receptors.

With high-frequency stimulation other events occur as described in the text

Induction of Long-Term PotentiationInduction of Long-Term Potentiation

Expression of Long-Term PotentiationExpression of Long-Term Potentiation

Filopodia

Growth of dendritic spines in response to synaptic stimulation in a brain slice. The neuron was filled with enhanced GFP by viral transfection and im

aged with two-photon laser scanning microscopy.

Dendritic Spines Growth

Water Maze Learning

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.

Properties of LTP

(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.

Different Plasticities In Hippocampus

Induction Mechansim For Hippocampal LTD

Long-Term Plasticity in CerebellumLong-Term Plasticity in Cerebellum

Cerebellar Structure

Whole-cell recording in Purkinej cells and LTDWhole-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

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.

Neuronal Plasticity

•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 collateral-commissural 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.

Key ReferencesKey References

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