COURSE:
TOPIC: Complex Receptors
LECTURER: Dr. Andrew P. Bendrups, School of Human Biosciences
These notes are about the discovery of the NMDA receptor and why it is so interesting and important. They do not go to the cutting edge of this research, but rather present a historical overview.
NMDA is N-methyl-D-aspartate, an amino acid which binds selectively to a special type of glutamate receptor (glutamate is an excitatory amino acid neurotransmitter in many parts of the CNS). The story starts at the beginning of this century when the concept of the neurone was still new and the existence of the chemical synapse was contraversial. Pavlov was experimenting with his dogs and discovered what we call classical conditioning.
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Pavlov found that if he rang a bell a few seconds before presenting meat to his dogs, after many repetitions the dogs began to salivate just on hearing the bell ring. In the jargon in this field, the meat is called the unconditioned stimulus (UCS) and the bell the conditioned stimulus (CS), meaning that the bell stimulus initiates a learning process (conditioning).
Pavlov's finding implied either that a new neural pathway from the hearing system to the salivary control system had been forged, or that a preexisting but nonfunctional connection (or near-connection) had become functional. The second alternative is the most likely: it is difficult to conceive of a mechanism whereby a new connection over distance could be formed as a result of simple pairing of two stimuli.
An influential psychologist Donald Hebb proposed a hypothetical way in which such types of learning (associative learning) could occur.
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Hebb proposed (to paraphrase his words using modern jargon) that if a neurone A took part in firing another neurone B, then a plastic change would occur in the synapse between neurone A and B, such that the connection between A and B would be strengthened.
We can assume that neurone B has other connections which make it fire, and that neurone A initially produces only a weak or no response. The key point is that neurone A has to be active ("trying to fire neurone B") at the same time that neurone B is undergoing action potentials (i.e. "firing")
This model in principle explained conditioning and other sorts of associative learning (e.g. learning by reward), where two sorts of synaptic input might interact. Memory is thus defined as a change in synpatic strength (or synaptic "weight"). The precise cellular mechanisms of learning remained to be elucidated.
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Much later, Eric Kandel and others studied the mechanisms of learning in the sea slug Aplysia, because of its simple nervous system.
The gill withdrawal reflex was used a model for classical conditioning. A light touch to the animal's syphon (CS) initially initiated a weak withdrawal, but after pairing in time with an electric shock to the tail (UCS), the withdrawal response was greatly enhanced and remained so. The UCS had to follow the CS immediately for maximal learning effect.
The plastic change was localized to the sensory neurones from the syphon. The mechanism was not Hebbian but similar in principle: it involved "temporally contiguous" activation of the sensory neurone (CS) and a modulatory synapse (UCS), with a presynaptic rather than postsynaptic connection (as in a classic Hebb synapse). The ultimate mechanism, activity dependent facilitation, proved to be biochemical.
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Kandel called the learning mechanism in Aplysia's gill withdrawal "activity dependent presynaptic facilitation" because of the specific anatomical arrangement in this system.
In Aplysia, the UCS alone produced a modest long-lasting enhancement of the reflex via production of cAMP as second messenger (which in turn induced a long-term modification of a K channel in the nerve ending, leading to prolonged APs and enhanced neurotransmitter release...). This effect is a type of non-associative learning termed "sensitization".
Pairing in time of the CS with the CS produced a much greater enhancement (associative learning) and was linked to entry of Ca into the nerve ending when it fired (as is usual for nerve endings since Ca entry triggers transmitter release). The biochemistry was found to involve Calmodulin and cAMP.
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A proposed mechanism for associative learning in Aplysia involves interaction between Calmodulin ( a Ca-binding enzyme) and a membrane-bound "catalytic unit" which synthesizes cAMP.
Binding of the modulatory transmitter alone activates cAMP synthesis, but only weakly. This acounts for sensitization of the withdrawal reflex.
When the nerve ending fires (e.g. due to sensory input, or direct stimulation), Ca enters and activates Calmodulin which then binds to the catalytic unit, "priming" it for maximal action. For a brief time, the modulatory transmitter is now able to exert a very strong effect, resulting in a long-lasting potentiation of transmitter release from the synapse, due to the actions of cAMP (see references for more detail).
More recently it has been discovered that the increased levels of cAMP also activate a protein kinase enzyme, which eventually acts via the nucleus of the neurone to stimulate synaptic sprouting and thus the consolidation of a long-term memory.
This mechanism provided a biochemical explanation for the requirement of temporal contiguity in associative learning, at least in the mollusc! The NMDA receptor may play a similar role in mammals: hence the excitement about its discovery.
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The NMDA receptor binds glutamate, but this has no effect unless another condition is satisfied. The lack of effect is because, at the "resting" membrane potential, the NMDA receptor's channel is blocked by Mg.
Strong depolarization of the postsynaptic membrane gets rid of the Mg, by electrostatic repulsion. If glutamate now binds, while the cell is depolarized, Ca is able to enter the NMDA channel. The entry of Ca then does things which ultimately lead to strengthening of the synapse, not by changing the NMDA receptor, but possibly by changing another glutamate receptor (the "Q" or "AMPA" receptor) and probably by altering the presyaptic terminal via a "retrograde messenger". Calmodulin and other enzymes influenced by Ca have been implicated.
This fits nicely with the ideas of Hebb: the NMDA receptor detects the coincidence of synaptic activation and postsynaptic depolarization.
The NMDA receptor is an elegant evolutionary device which the mammalian nervous system may use to learn associations between external events which are related in time. Such events are important because they may be related as cause and effect.
Memory of cause and effect allows prediction of the future, an important advantage for survival of a species. Different mechanisms have evolved, but a common principle of "molecular detection" appears to hold. Whether this involves cooperative binding of two substances (e.g. Calmodulin and a regulatory transmitter) or detection of membrane charge coupled with transmitter binding, the effect is the same.
The processes which actually store the long-term change in synaptic effect are complex and are not yet fully understood: for all its importance, coincidence detection is merely the switch which turns them on...
Abrams, T. W. & Kandel, E. R. (1988)*. Is contiguity detection in classical conditioning a system or a cellular property? Learning in Aplysia suggests a possible molecular site. Trends in Neuroscience, 11, 128-135
Collingridge, G. L. & Bliss, T. V. P. (1995). Memories of NMDA receptors and LTP. Trends in Neuroscience, 18, 54-56.
*See also other papers in Volume 11, No. 4 of TINS, dedicated to "Learning & Memory"