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Memory and the brain
Forgetting and Amnesia

HelpLong-term potentiation (LTP)Neurotransmitter Systems IV: LTP, LTD & the Hebbian synapseCell and Molecular Biological Studies of Memory Storage (Kandel)
Souvenirs, souvenirsUn commutateur moléculaire pour stocker les souvenirsThe chemistry of forgettingAnatomie de l'hippocampe
The Power of the Memory MoleculeScientists Identify Machinery That Helps Make MemoriesConstructions et déconstructions permanentes des connexions entre les neuronesMIT Team Discovers Memory Mechanism
Un gène pour la mémoireLink : Why Sleep Is Needed To Form Memories Link : Watching Molecules Morph into Memories
Sylvain Williams: The Septo-hippocampal LabEric kandel, prix nobel de médecine
Original modules
Experiment Module: The Effect of an Enriched Environment on MemoryThe Effect of an Enriched Environment on Memory
 Experiment Module: Inducing LTP Experimentally Inducing LTP Experimentally
 Experiment Module: Confirming the Roles of an Ion, a Second Messenger, and an Enzyme in Long-Term Potentiation Confirming the Roles of an Ion, a Second Messenger, and an Enzyme in Long-Term Potentiation
Experiment Module: Specificity and Associativity of LTP Specificity and Associativity of LTP

The spines on post-synaptic dendrites form separate compartments to isolate biochemical reactions that occur at some synapses but not at others. This anatomical specialization probably helps to ensure a certain specificity in neural connections.

“Silent synapses” are another mechanism that was discovered in the mid-1990s and that may contribute to long-term potentiation (LTP). These synapses are physically present, but under normal conditions do not contribute to synaptic transmission.

Some of these silent synapses have been found in the hippocampus. They appear to have receptors for NMDA but not for AMPA. It is thought that these synapses may be activated during LTP and thus help to strengthen the synaptic response. The discovery that after LTP, these synapses do display an electrical current associated with AMPA channels suggests that some newly synthesized AMPA receptors may be inserted into the post-synaptic membrane.

Linked Module: Silent Synapse Activation with LTP

Long-term potentiation (LTP) is a process in which synapses are strengthened. It has been the subject of much research, because of its likely role in several types of memory. LTP is the opposite of long-term depression (LTD). In LTP, after intense stimulation of the presynaptic neuron, the amplitude of the post-synaptic neuron’s response increases. The stimulus applied is generally of short duration (less than 1 second) but high frequency (over 100 Hz). In the postsynaptic neuron, this stimulus causes sufficient depolarization to evacuate the magnesium ions that are blocking the NMDA receptor, thus allowing large numbers of calcium ions to enter the dendrite.

These calcium ions are extremely important intracellular messengers that activate many enzymes by altering their conformation. One of these enzymes is calmoduline, which becomes active when four calcium ions bind to it. It then becomes Ca2+/calmodulin, the main second messenger for LTP. Ca2+/calmodulin then in turn activates other enzymes that play key roles in this process, such as adenylate cyclase and Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). These enzymes in turn modify the spatial conformation of other molecules, usually by adding a phosphate ion to them. This common catalytic process is called phosphorylation.

Thus, the activated adenylate cyclase manufactures cyclic adenosine mono-phosphate (cAMP), which in turn catalyzes the activity of another protein, kinase A (or PKA). In other words, there is a typical cascade of biochemical reactions which can have many different effects.

For example, PKA phosphorylates the AMPA receptors, allowing them to remain open longer after glutamate binds to them. As a result, the postsynaptic neuron becomes further depolarized, thus contributing to LTP.

Other experiments have shown that CREB protein is another target of PKA. CREB plays a major role in gene transcription, and its activation leads to the creation of new AMPA receptors that can increase synaptic efficiency still further.

The other enzyme activated by Ca2+/calmodulin, CaM kinase II, has a property that is decisive for the persistence of LTP: it can phosphorylate itself! Its enzymatic activity continues long after the calcium has been evacuated from the cell and the Ca2+/calmodulin has been deactivated.

CaM kinase II can then in turn phosphorylate the AMPA receptors and probably other proteins such as MAP kinases, which are involved in the building of dendrites, or the NMDA receptors themselves, whose calcium conductance would be increased by this phosphorylation.


To give some idea of the complexity of the metabolic sequences responsible for LTP, we will mention three of the other enzymes currently being studied. Protein kinase C (PKC) appears to phosphorylate AMPA receptors at the same site as CaM kinase II. Inhibitor 1 (ou I1) seems to be activated by PKA and prevent phosphatase 1 from dephosphorylating AMPA receptors. And tyrosine kinase SRC may be activated directly by the AMPA receptors, and then phosphorylate the NMDA receptors.

LTP involves at least two phases: establishment (or induction), which lasts about an hour, and maintenance (or expression), which may persist for several days. The first phase can be experimentally induced by a single, high-frequency stimulation. It involves the activity of various enzymes (kinases) that persist after the calcium is eliminated, but no protein synthesis.  To trigger the maintenance phase, however, a series of high-frequency stimuli must be applied. Unlike the establishment phase of LTP, the maintenance phase requires the synthesis of new proteins–for example, the ones that form the receptors and the ones that contribute to the growth of new synapses (another phenomenon that occurs during the maintenance phase).

In addition to all of the post-synaptic mechanisms involved in the establishment of LTP, it has long been postulated that some presynaptic modifications occur during the ensuing maintenance phase. But certain modifications, such as an increase in the amount of glutamate released by the presynaptic neuron, would imply the presence of a retrograde messenger that goes back to this neuron and modifies it. Because nitric oxide (NO) is a gas in its natural state, and can thus diffuse through cell membranes, it would be an ideal candidate for this role. But its involvement is still the subject of much debate and controversy.

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