medial superior olive in mammals. Synaptic plasticity and associativity In 1949, Donald Hebb postulated that synaptic efficiency will increase through repeated and persistent stimulation of a postsynaptic cell by a presynaptic cell. This is often informally summarized as "cells that fire together, wire together". The theory was validated in part by the discovery of long-term potentiation. Studies of LTP on multiple presynaptic cells stimulating a postsynaptic cell uncovered the property of associativity. A weak neuronal stimulation onto a pyramidal neuron may not induce long-term potentiation. However, this same stimulation paired with a simultaneous strong stimulation from another neuron will strengthen both synapses. This process suggests that two neuronal pathways converging on the same cell may both strengthen if stimulated coincidentally. Molecular mechanism of long-term potentiation LTP in the hippocampus requires a prolonged depolarization that can expel the Mg2+ block of postsynaptic NMDA receptors. The removal of the Mg2+ block allows the flow of Ca2+ into the cell. A large elevation of calcium levels activate protein kinases that ultimately increase the number of postsynaptic AMPA receptors. This increases the sensitivity of the postsynaptic cell to glutamate. As a result, both synapses strengthen. The prolonged depolarization needed for the expulsion of Mg2+ from NMDA receptors requires a high frequency stimulation. Associativity becomes a factor because this can be achieved through two simultaneous inputs that may not be strong enough to activate LTP by themselves. Besides the NMDA-receptor based processes, further cellular mechanisms allow of the association between two different input signals converging on the same neuron, in a defined timeframe. Upon a simultaneous increase in the intracellular concentrations of cAMP and Ca2+, a transcriptional coactivator called TORC1 (CRTC1) becomes activated, that converts the temporal coincidence of the two second messengers into long term changes such as LTP. This cellular mechanism, through calcium-dependent adenylate cyclase activation, might also account for the detection of the repetitive stimulation of a given synapse. Adenylyl cyclase (also commonly known as adenyl cyclase and adenylate cyclase) has been implicated in memory formation as a coincidence detector Molecular mechanism of long-term depression Long-term depression also works through associative properties although it is not always the reverse process of LTP. LTD in the cerebellum requires a coincident stimulation of parallel fibers and climbing fibers. Glutamate released from the parallel fibers activates AMPA receptors which depolarize the postsynaptic cell. The parallel fibers also activate metabotropic glutamate receptors that release the second