Long-term potentiation

In neuroscience, long-term potentiation (LTP) is the strengthening (or potentiation) of the connection between two nerve cells which lasts for an extended period of time (minutes to hours in vitro and hours to days and months in vivo). LTP can be induced experimentally by applying a sequence of short, high-frequency stimulations to nerve cell synapses. The phenomenon was discovered in the mammalian hippocampus by Terje Lmo in 1966 and is commonly regarded as the cellular basis of memory.

History

Early theories of learning

By the turn of the 19th century, neurobiologists had good reason to believe that memories were generally not the product of new nerve cell growth. Scientists generally believed that the number of neurons in the adult brain (roughly 10¹¹) did not increase significantly with age. With this realization came the need to explain how memories were created in the absence of new cell growth.

Among the first neuroscientists to suggest that learning was not the product of new cell growth was the Spanish anatomist Santiago Ramn y Cajal. In 1894 he proposed that memories might be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication. Hebbian theory, introduced by Donald Hebb in 1949, echoed Ramn y Cajal's ideas, and further proposed that cells may grow new connections between each other to enhance their ability to communicate:

Let us assume that the persistence or repetition of a reverberatory activity (or "trace") tends to induce lasting cellular changes that add to its stability.... 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.

Similarly, memories may be forgotten through the weakening or loss of connections. For example, a man might be startled by the sound of a car alarm outside. Sensory cells in the ear record the sound and send it to the brain where it activates neurons that control the man's muscles. But as the blaring alarm continues, those connections are weakened so that the alarm no longer causes the man to be startled.

These theories about memory formation were unfortunately foresighted. Neuroscientists were simply not yet equipped with the neurophysiological techniques necessary for elucidating the biological underpinnings of learning in animals. These skills would not come until the latter half of the 20th century, at about the same time as the discovery of long-term potentiation.

Discovery of long-term potentiation

LTP was first observed by Terje Lmo in 1966 in the Oslo, Norway, laboratory of Per Andersen^{[20]. He tested the spatial memory of two groups of rats, one whose hippocampi were bathed in the NMDA receptor blocker APV, and the other acting as a control group. (Incidentally, the hippocampus, where LTP was originally observed, is required for spatial learning.) Both groups were then subjected to the Morris water maze, in which rats were placed into a pool of murky water and tested on how quickly they could locate a platform hidden beneath the water's surface.}

Rats in the control group were able to locate the platform and escape from the pool, whereas the ability of APV-treated rats to complete the task was significantly impaired. Moreover, when slices of the hippocampus were taken from both groups of rats, LTP was easily induced in controls, but could not be induced in the brains of APV-treated rats. This provided some evidence that the NMDA receptor — and thus LTP — was somehow involved with at least some types of learning and memory.

Similarly, Susumu Tonegawa has demonstrated that a specific region of the hippocampus, namely CA1, is crucial to the formation of spatial memories [21]. So-called place cells located in this region are responsible for creating "place fields" of the rat's environment, which may be roughly equated with maps of the rat's surroundings. The accuracy of these maps determines how well a rat learns about its environment, and thus how well it can navigate about it.

Tonegawa found that by impairing the NMDA receptor, specifically by genetically removing the NMDAR1 subunit in the CA1 region, the place fields generated were substantially less specific than those of controls. That is, rats produced faulty spatial maps when their NMDA receptors were impaired. As expected, these rats performed very poorly on spatial tasks compared to controls, providing more support to the notion that LTP is the underlying mechanism of spatial learning.

Doogie mice

Enhanced NMDA receptor activity in the hippocampus has also been shown to produce enhanced LTP and an overall improvement in spatial learning. Joe Tsein produced a line of mice with enhanced NMDA receptor function by overexpressing the NR2B subunit in the hippocampus [22]. These mice, nicknamed "Doogie mice" after the precocious doctor Doogie Howser, had larger long-term potentiation and excelled at spatial learning tasks, once again suggesting LTP's involvement in the formation of hippocampal-dependent memories.

Related topics

• learning
• long-term depression
• memory

Notes

2. ^ PMID 12740104
3. ^ Mayer ML, Westbrook GL, Guthrie PB (1984) "Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones". Nature 309 (5965), 261-3. PMID 6325946
4. ^ Rogan MT, Staubli UV, LeDoux JE (1997) "Fear conditioning induces associative long-term potentiation in the amygdala". Nature 390 (6660), 604-7. PMID 9403688
5. ^ Artola A, Singer W (1987) "Long-term potentiation and NMDA receptors in rat visual cortex". Nature 330 (6149), 649-52. PMID 2446147
6. ^ Weisskopf MG, Bauer EP, LeDoux JE (1999) "L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala". J Neurosci 19 (23), 10512-9. PMID 10575047
7. ^ Lu YF, Kandel ER, Hawkins RD (1999) "Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus". J Neurosci 19 (23), 10250-61. PMID 10575022
8. ^ Huang YY, Kandel ER (1994) "Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization". Learn Mem 1 (1), 74-82.
9. ^ Kojima N, Wang J, Mansuy IM, Grant SG, Mayford M, Kandel ER (1997) "Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing Fyn transgene". Proc Natl Acad Sci U S A 94 (9), 4761-5. PMID 9114065
10. ^ Malinow R, Schulman H, Tsien RW (1989) "Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP". Science 245 (4920), 862-6. PMID 2549638
11. ^ Otmakhova NA, Otmakhov N, Mortenson LH, Lisman JE (2000) "Inhibition of the cAMP pathway decreases early long-term potentiation at CA1 hippocampal synapses". J Neurosci 20 (12), 4446-51. PMID 10844013
12. ^ English JD, Sweatt JD (1997) "A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation". J Biol Chem 272 (31), 19103-6. PMID 9235897
13. ^ Sweatt JD (2001) "The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory". J Neurochem 76 (1), 1-10. PMID 11145972
14. ^ PMID 10545144
15. ^ Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN (1989) "An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation.". Nature 340 (6234), 554-7.
16. ^ Sweatt JD (1999) "Toward a molecular explanation for long-term potentiation.". Learn Mem 6 (5), 399-416.
17. ^ Esteban JA (2003) "AMPA receptor trafficking: a road map for synaptic plasticity.". Mol Interv 3 (7), 375-85.
18. ^ Otmakhova NA, Otmakhov N, Mortenson LH, Lisman JE (2000) "Inhibition of the cAMP pathway decreases early long-term potentiation at CA1 hippocampal synapses.". J Neurosci 20 (12), 4446-51.

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