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Molecular Mechanisms of Learning and Memory Ying Shen, Ph.D. Voice: 0571-88208240 Email: yshen@zju.edu.cn Department of Neurobiology Zhejiang University School of Medicine. Plasticity Is Hot!. Aplysia Californica. Eric R. Kandel. Why Aplysia ?. Cellular Mechanism of Habituation.
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Molecular Mechanisms of Learning and Memory Ying Shen, Ph.D. Voice: 0571-88208240 Email: yshen@zju.edu.cn Department of Neurobiology Zhejiang University School of Medicine
AplysiaCalifornica Eric R. Kandel
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 Xjand Ytare presynaptic and postsynaptic activities, respectively, and e > 0 is learning rate.
LTP -induced changes can last for many days Population spike
Long-Term Potentiation in Hippocampus 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.
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
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.
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 • 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. • 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. • 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.
200 pA 20ms Whole-cell recording in Purkinej cells and LTD
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 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.
