Long term potentiation

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Long-term potentiation (LTP) is a permanent increase in synaptic coupling as a result of increased arousal. LTP studies are often done on histological slices of the hippocampus , an important organ for learning and memory . In such studies, electrical recordings of nerve cell activity are made and presented on graphs like this one. It compares the response of a nerve cell after LTP with one without LTP. After LTP, the response to electrical excitation at a synapse is usually stronger over the long term. X-axis: time in minutes. Y-axis: Increase in the post-synaptic (behind the gap, at the target neuron) electrical excitation potential in millivolts per millisecond (mV / ms).

The long-term potentiation (English long-term potentiation, LTP ) is an at synapses of neurons observed phenomenon. It represents a form of synaptic plasticity . LTP is a long-term strengthening ( potentiation ) of synaptic transmission.

LTP and learning

A synapse is repeatedly excited.
Increased number of dendritic receptors.
Increased number of neurotransmitters.
A stronger coupling of the neurons.

From the point of view of neurophysiology and neuropsychology there is a connection between the learning of skills and the changes taking place in a neural network , which has a morphologically tangible correlate in the form of changed synaptic connections in its network . New connections are created and previous connections canceled if skills are learned or improved through repeated activity patterns or training, for example new words or word meanings are learned.

When speaking, for example, the association cortex gives rise to the idea of pronouncing a word, and a special network is activated that sends out a characteristic pattern of action potentials . Only after further interconnections these signals eventually reached by motor neurons and muscle cells of various muscles of different muscle groups. Their contraction, coordinated and controlled according to the development of force and time sequence, requires a highly differentiated, time-coordinated pattern of the neural signal sequences necessary for this. This has to be learned - how to pronounce a word correctly. The changes in synapses that take place during the necessary neural remodeling processes are an expression of their malleability, called synaptic plasticity . At the neuron level , learning is the activity-dependent change in interconnection patterns and functional processes. These activity-dependent neuronal changes are realized in different ways, whereby the mechanisms can be developed to different degrees in different neurons of the cerebral cortex areas , the limbic system , the cerebellum and the brain stem . These include B. the

  • presynaptic gain ( presynaptic enhancement = facilitation )
  • post-tetanic potentiation,
  • synaptic depression
  • as well as long-term potentiation (LTP).

LTP is understood to be a long-lasting amplification of synaptic transmission. The best-studied form of LTP occurs at the synapses of the pyramidal cells in the CA1 region of the hippocampus with the Schaffer collaterals . In humans, the hippocampus is necessary for the creation of episodic memories. It is known from mice and rats that the hippocampus is necessary for spatial learning.

For a long time, the direct connection between LTP at the CA1 synapses and learning was still hypothetical, but in 2006 experimental evidence was provided that firstly, spatial learning in rats generates LTP and, secondly, preventing the maintenance of the LTP from deleting existing spatial memory contents Consequence.

LTP in the development of the nervous system

During embryonic development, significantly more neuronal connections are created than will ultimately survive to adult humans. About a third of all neurons perish during development. This redundancy makes sense because a kind of competition arises between the neurons that only the nerve cells that establish connections to the right goals in the brain survive.

For example, have axons from the primary motor cortex to motor neurons in the spinal cord project.

Misdirected neurons die. This happens due to the lack of special neurotrophins . Furthermore, of the properly directed neurons, only those with the most stable synaptic connections survive. Stable connections are strengthened, this happens through LTP, while weak connections are decoupled, this happens through long-term depression (LTD)

Cellular mechanism of NMDA-dependent long-term potentiation

In many areas of the brain, u. a. In the cerebral cortex , the amygdala , the cerebellum (cerebellum) and the hippocampus , glutamatergic synapses occur, which have some special characteristics. The most important feature is the presence of AMPA receptors (subspecies of glutamate receptors) and N -methyl-D-aspartate receptors ( NMDA receptor ). The latter stands out from the other ionotropic glutamate receptors in that, on the one hand, it has a very high permeability for calcium ions and, on the other hand, in the case of a hyperpolarized membrane, it is closed from the outside by a magnesium ion. In addition to the NMDA-dependent LTP, there are also NMDA-independent forms of the LTP. In the NMDA-dependent LTP, the following events occur at the synapse:

  1. Excitation of the postsynaptic membrane by glutamate leads to its depolarization by the AMPA receptors, creating an excitatory postsynaptic potential (EPSP) .
  2. Only high-frequency repeated depolarization (25–200Hz) or simultaneous depolarization through several converging, coincident synapses leads to the charge repulsion of the Mg ion on the NMDA receptor and its opening. This leads to an influx of calcium into the postsynapse and increased intracellular Ca concentration.
  3. Calcium activates protein kinase C and Ca / calmodulin- dependent kinases (without CaMKII, no LTP).
    1. This leads to increased incorporation of AMPA and kainate receptors (both glutamate receptors),
    2. existing AMPA receptors are phosphorylated by the CaMKII, increasing their permeability to ions. In this way, the postsynaptic membrane is sensitized for glutamate.
    3. Furthermore, there is a physical growth of dendritic spines (spines) by modification of actin - cytoskeleton . Such changes are seen as the basis for the "late phase" of LTP, which lasts for hours, days, or weeks. The stabilization of the enlargement of a dendritic thorn process correlates with an increase in the size of the postsynaptic density and the axonal bouton. At the molecular level, there is an increase in the skeletal proteins PSD-95 and Homer1c.
    4. It has long been discussed whether presynaptic changes also contribute to LTP. These changes would have to be triggered by a retrograde messenger substance that acts back on the presynaptic terminals from postsynaptic cells. In particular, five classes of messenger substances , of which retrograde effects are known, are examined: lipids , gases, peptides , conventional neurotransmitters and growth factors .

Consequences for learning theory

LTP can create self-reinforcing cycles (feed-forward loops). From a learning theory perspective , the following points are interesting:

  • NMDA receptors are coincidence receptors, which means that LTP arises to a greater extent when several neurons are fired synchronously. For example, during sleep , a strong synchronization of nerve cell groups can be observed. The Papez circle is a chain of brain regions that are supposed to be involved in the storage of information.
  • NMDA neurons are modified by the ascending reticular activation system (ARAS). The transmitters noradrenaline (from the locus caeruleus ), serotonin (from the raphe nuclei ), acetylcholine (from the nucleus basalis by Theodor Meynert ) and dopamine (from the substantia nigra ) mediate the closure of potassium channels and via the stimulation of their receptors cause a depolarization . Depolarized cells are more sensitive to glutamate signals. Attention therefore plays a major role in learning processes.
  • A weak activation of the NMDA synapses only leads to a slight increase in intracellular Ca concentration. This causes exactly the opposite of LTP, namely long-term depression (LTD) .

history

The Spaniard Santiago Ramon y Cajal had the idea as early as 1894 that memory was formed by strengthening the connection between existing neurons, which would improve their transmission efficiency.

Around 1900 it was believed that memory was not the product of new nerve cell growth and that the number of neurons in an adult's brain did not increase significantly with age.

Donald O. Hebb (1949) took up these ideas, but went one step further: cells would also form new connections to improve the effectiveness of their transmission ( Hebb's rule ): If an axon of cell A excited cell B and repeated as well as contributing permanently to the generation of action potentials in cell B, this results in growth processes or metabolic changes in one or both cells, which have the effect that the efficiency of cell A with regard to the generation of an action potential in cell B is greater. (Colloquially: What fires together, wires together. )

The theories mentioned could not be proven at their time, as the corresponding neurophysiological methods were only available in the second half of the 20th century.

LTP was discovered by Terje Lømo in 1966 and is still an important subject of research today (e.g. development of drugs that use the biological mechanisms of LTP to counter the effects of diseases such as Alzheimer's disease or Parkinson's disease ).

Terje Lømo performed a series of neurophysiological experiments in anesthetized rabbits to investigate the role of the hippocampus in relation to short-term memory (STC). He found that a single impulse of electrical stimulation of the perforated tract produced an excitatory postsynaptic potential (EPSP) in the dentate gyrus . However, what was unexpected for Lømo was the observation that a short, high-frequency series of excitation pulses triggered a long-lasting enlargement of the EPSP. This change was then called LTP. Together with his colleague Timothy Bliss, Lømo published the first properties of LTP in the hippocampus of rabbits in 1973.

Individual evidence

  1. ^ Michael A. Paradiso, Mark F. Bear, Barry W. Connors: Neuroscience: Exploring the Brain . Lippincott Williams & Wilkins, Hagerstwon, MD (USA) 2007, ISBN 978-0-7817-6003-4 , pp. 718 .
  2. ^ J. Whitlock, A. Heynen, M. Shuler, M. Bear: Learning induces long-term potentiation in the hippocampus. In: Science. 313 (5790), 2006, pp. 1093-1097. PMID 16931756 .
  3. ↑ E. Pastalkova, P. Serrano, D. Pinkhasova, E. Wallace, A. Fenton, T. Sacktor: Storage of spatial information by the maintenance mechanism of LTP. In: Science. 313 (5790), 2006, pp. 1141-1144. PMID 16931766 .
  4. ^ LM Grover: Evidence for postsynaptic induction and expression of NMDA receptor independent LTP. In: Journal of neurophysiology. Volume 79, Number 3, March 1998, pp. 1167-1182. PMID 9497399 (free full text).
  5. ↑ S. Moosmang, N. Haider, N. Klugbauer, H. Adelsberger, N. Langwieser, J. Müller, M. Stiess, E. Marais, V. Schulla, L. Lacinova, S. Goebbels, KA Nave, DR Storm , F. Hofmann, T. Kleppisch: Role of hippocampal Cav1.2 Ca2 + channels in NMDA receptor-independent synaptic plasticity and spatial memory. In: The Journal of neuroscience: the official journal of the Society for Neuroscience. Volume 25, number 43, October 2005, pp. 9883-9892, doi: 10.1523 / JNEUROSCI.1531-05.2005 . PMID 16251435 (free full text).
  6. ^ D. Meyer, T. Bonhoeffer, V. Scheuss: Balance and Stability of Synaptic Structures during Synaptic Plasticity . In: Neuron . tape 82 , no. 2 , 2014, p. 430–443 , doi : 10.1016 / j.neuron.2014.02.031 , PMID 24742464 .
  7. ^ WG Regehr, MR Carey, AR Best: Activity-dependent regulation of synapses by retrograde messengers. In: Neuron. 63 (2), 2009, pp. 154-170, Review Article, Free Full Text Online. PMID 19640475
  8. ↑ Bruce Alberts , Alexander Johnson, Julian Lewis, David Morgan, Martin Raff , Keith Roberts, Peter Walter: Molecular Biology of the Cell , 6th Edition, Wiley-VCH Verlag, Weinheim 2017, ISBN 978-3-527-69845-5 , p 718, Preview of Google Books .
  9. ^ TV Bliss, T. Lomo: Long-lasting potentiation of synaptic transmission in the dentate area of ​​the anesthetized rabbit following stimulation of the perforant path. In: J Physiol. 232 (2), 1973, pp. 331-356, Free Full Text Online. PMID 4727084

literature

  • Eric R. Kandel et al. (Ed.): Neurosciences - An introduction. Spectrum Academic Publishing House, 1996, ISBN 3-86025-391-3 .
  • Dale Purves: Neuroscience. 3. Edition. Sinauer Associates, 2004, ISBN 0-87893-725-0 .
  • HT Blair, GE Schafe, EP Bauer, SM Rodrigues, JE LeDoux: Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning. In: Learn Mem. 8, 2001, pp. 229–242 (full text)