Learning and Memory

Plan

Intro

Q1 (a) Read the short extract below (adapted from a article on memory published in a prestigious journal; you do not need the reference), which clearly implys that the LTP is mechanism that underlines learning memory. Using the evidence presented in Book 5, Chapter 1, write a structured account (i.e. an essay) disusing the extent to which you agree with the implication, and reviewing the evidence for and against LTP as the synaptic basis of learning memory.

Introduction

Learning is the acquisition of new information and memory is the storage of such information. The neurobiological basis of learning and memory remain poorly understood but long-term potentiation (LTP) is a possible mechanism. LTP is a form of activity dependent synaptic enhancement, which allows synapses to become strengthened on the basis of their previous activity. It has been defined as “a long-term increase in the excitability of a neuron to a particular synaptic input caused by repeated high-frequency activity of that input”. Many researchers believe that LTP is a valid correlate for learning and memory due to the fact that it persists over time, as well as the fact that can be rapidly induced, is associative and depends on correlated presynaptic and postsynaptic activity. This account will review the neurobiological evidence for LTP as a mechanism, then go on to outline some of the evidence that it in fact is the neurobiological basis of learning and memory.

The neurological basis of Long Term Potentiation

The phenomenon of Long Term Potentiation (LTP) was originally chronicled by Bliss and Lomo in 1973; when they reported that stimulation of the perforant path leading to the dentate gyrus in the hippocampus of a rabbit caused a potentiation of the response in these cells. LTP can be generated by activating the afferent pathway such that a stable excitatory postsynaptic potential (EPSP) can be measured in the postsynaptic cell. If a conditioning tetanus (or conditioning train as Bliss and Lomo called it) is then applied, in the form of higher frequency stimulation, there is a subsequent potentiation of the synapse. This relies on both presynaptic and postsynaptic neurons being active at the same time, e.g. presynaptic stimulation in conjunction with postsynaptic depolarisation. The magnitude of the evoked conductance change in the synaptic membrane was found to be directly related to the effective conductance of the membrane and the magnitude of the potentiated EPSP.

Ordinarily hippocampal glutamatergic neurotransmission relies mainly on AMPA receptors, which allow sodium ion passage whenever bound by glutamate. However, in the conditions observed with LTP another glutamate receptor, NMDA, becomes effective. The postsynaptic depolarisation allows the receptor channel to open, freed from the magnesium ion that ordinarily blocks it, leading to a greater influx of calcium ions, to go with the sodium ions flowing in through the AMPA receptor channels. The calcium ions then affect calcium dependent kinase enzymes that alter the AMPA receptor so that it can allow more sodium ions to pass through in future.

The involvement ...

This is a preview of the whole essay

The involvement of calcium is supported by the fact that reducing the level or activity of intracellular calcium ions prevents LTP from being generated. This means that NMDA receptors are necessary for LTP but the subsequent transmission at the potentiated synapses involved AMPA receptors. It has also been shown that there is an increase in the number of AMPA receptors in potentiated synapses, but no increase in NMDA receptor number.

Evidence for LTP in learning and memory

Mice that have a mutation that mimics human Alzheimer’s disease (AD) are unable to support LTP in their hippocampal neurons. As AD patients are known to experience difficulties in forming new memories there would appear to be a correlation between LTP and memory formation.

It has been shown that activation of NMDA receptors induces synaptic potentiation and enhances memory. Mice can be trained using the principles of classical conditioning to freeze in response to a tone; the tone having initially been paired with a foot shock to cause the freezing fear response. The freezing to the tone has been shown to be a learned response associated with enhanced synaptic potentials. Further evidence for this to be an LTP response can be seen in the fact that the enhanced synaptic response exists for as long as the behavioural response, and is not mirrored in animals that hadn’t been trained according to the same classical conditioning methodology. Finally, blockade of NMDA receptors prevents either the behavioural response or the synaptic enhancement, indicating that NMDA receptors are crucial in the process.

Evidence for the involvement of NMDA receptors in new learning can be seen in the Morris water maze experiments. Mice placed in water normally learn to find a submerged platform, initially by trial and error, and latterly by utilising memories of the location. It is this learning of the location that is aberrant in mice given NMDA receptor antagonists as they are unable to utilise spatial cues appropriately to orient themselves in the water. Figure 1 below shows the difference in the exploration of mice who were able to learn and those given the NMDA antagonist D,L-AP5. It can be seen that the control mice home in on the platform much more effectively than the random pattern of the D,L-AP5 mice.

Figure 1 . The difference in performance of mice who could learn (left control) and those who could not (right D,L-AP5)

The reason for the involvement of NMDA receptors may be related to their role in the synthesis of proteins. Ordinarily NMDA receptors identify newly potentiated synapses via synaptic tagging and activate local signalling which stimulates new proteins to be synthesised. It has been suggested that the new proteins synthesised might actually be the AMPA receptors required to mediate the enhanced synaptic response seen in LTP synapses.

Evidence against LTP as the correlate for learning and memory

Whilst much of the evidence supports LTP as the correlate of learning and memory there are dissenters. It has been shown that LTP induced in a number of areas of the hippocampus is not actually a reliable model and mice are still able to learn even though the induction of LTP is not possible in their brains. It has also been suggested that the only reason that models of LTP support learning so well is that they have been designed to do so, and thus they are only fulfilling their design criteria, rather than more stringent scientific criteria.

Conclusion

There does seem to be logical evidence that LTP is involved in the NMDA facilitated induction of AMPA receptors in order to potentiate synaptic responses. However Murphy and Naish appear only to present evidence that is supportive and largely ignore anything that isn’t. If one is to search more further afield it becomes obvious that the evidence that exists is largely correlational. Whilst it does show cause and effects it cannot be shown that they are directly instrumental upon each other. In fact TVP Bliss, one of the original researchers, actually stated that LTP could not be proven (or disproven) as the basis of learning and memory. Similarly most neuroscientists are very reluctant to categorically state that LTP is the basis of learning and memory, as shown by Stevens’ straw poll of only 60% being willing to agree when forced to make a choice. So LTP remains a suitable model for learning and memory, but an unproven one.

References

Abraham, W.C. 2003, “How long will long-term potentiation last?”, Philosophical transactions of the Royal Society of London. Series B: Biological sciences, vol. 358, no. 1432, pp. 735-744.

Bliss, T.V. & Lomo, T. 1973, “Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path”, The Journal of physiology, vol. 232, no. 2, pp. 331-356.

Carlson, N. 2001, “Learning and Memory: Basic Mechanisms” in Physiology of Behaviour, 7th edn, Allyn and Bacon, Boston, pp. 423-465.

Holscher, C. 1997, “Long-term potentiation: a good model for learning and memory?”, Progress in neuro-psychopharmacology & biological psychiatry, vol. 21, no. 1, pp. 47-68.

Morris, R.G. 2003, “Long-term potentiation and memory”, Philosophical transactions of the Royal Society of London. Series B: Biological sciences, vol. 358, no. 1432, pp. 643-647.

Murphy, K. & Naish, P. 2006, “Learning and Memory” in Learning and Language, eds. S. Datta, I. Lyon & B. MacKintosh, et al, 2nd edn, The Open University, Milton Keynes, pp. 1-48.

Stevens, C.F. 1998, “A million dollar question: does LTP = memory?”, Neuron, vol. 20, no. 1, pp. 1-2.