English: (A) The induction of canonical forms of both LTP and LTD is triggered by activation of the NMDA class of glutamate receptor. This ionotropic receptor detects the coincidence of presynaptic and strong postsynaptic activity by a mechanism that involves both the binding of transmitter and depolarization-induced repulsion of the Mg2+ ions that block its ionophore at near-resting membrane potentials. In its unblocked state Ca2+ ions are able to permeate the channel, gaining access to Ca2+-dependent processes in the spine and triggering synaptic plasticity. (B) Ca2+ binds to Ca2+/calmodulin which, in turn activates numerous kinases and phosphatases, including CaMKII, PKC and Calcineurin (PP2B) directly and PKA and PP1 indirectly. The balance of kinase and phosphatase activity depends on the concentration and temporal profile of the postsynaptic Ca2+ transient (including Ca2+ released from intracellular stores). The Ca2+ transient determines the polarity of the induced plasticity, with low and prolonged Ca2+ transients inducing LTD and brief, steeper transients inducing LTP. (C) One means by which LTP is expressed is through phosphorylation of the AMPA receptor, an ionotropic glutamate receptor that mediates baseline chemical transmission at excitatory synapses in the CNS. Phosphorylation by CaMKII enhances the conductance of these channels. LTD, by contrast, results, in part, from the dephosphorylation of the AMPA receptor by phosphatases. (D) Trafficking of AMPA receptors plays a major role in the expression of LTP and LTD by increasing or decreasing the number of receptors in the postsynaptic membrane. (E) Presynaptic mechanisms leading to a sustained increase in the probability of transmitter release also contribute to the expression of LTP. The relative contributions of pre- and post-synaptic mechanisms may vary at different times after induction and also across different classes of synapse. Since induction of LTP and LTD is controlled by the post-synaptic NMDA receptor, any presynapic component of expression requires a retrograde messenger that can signal to the pre-synaptic terminal that coincidence has occurred. Two candidates are nitric oxide (NO) and endocannabinoids (EC). (F) A second form of LTD that has been much studied is dependent on group 1 metabotropic glutamate receptors (mGluR). Glutamate binding to this receptor initiates a signal cascade, involving the breakdown of the membrane lipid PIP2 by phospholipase C (PLC) to the important signaling molecules IP3, which releases Ca2+ from Ca2+ stores (not shown) and diacylglycerol (DAG), which leads to the activation of the calcium sensitive kinase PKC. This enzyme then phosphorylates the AMPA receptor but in such a manner that the conductance is reduced. An offshoot is the production of NO. (G) Brain-derived neurotrophic factor (BDNF) plays a complicated role in both LTP and LTD and contributes in different ways to short-term and long-term plasticity. (H) Longer-lasting ‘late’ forms of LTP and LTD, persisting for more than a few hours, require the synthesis of new proteins, either through novel gene transcription or through initiation of local translation of existing transcripts. Novel gene expression requires signaling to the nucleus from newly potentiated or depressed synapses. A major player in this process is the cAMP-dependent signaling cascade initiated by calcium influx and involving adenylyl cyclase (AC) and cAMP-dependent kinase (PKA), which also acts directly on the AMPA receptor in LTP expression. Catecholaminergic modulatory input plays a major role in determining the longevity of LTP and LTD, through interaction with AC which increases levels of cAMP and thereby activates PKA. PKA then sets in action a chain of signals that leads to the expression of new transcripts which, in turn are translated into proteins contributing to the long-term expression of synaptic plasticity. This signaling pathway has been a major recent target of attempts to find nootropic substances. (I) There are parallel signaling pathways, involving mitogen activated protein kinases (MAPK), that also result in the synthesis of new proteins. However, in this case existing transcripts are locally translated into proteins, without further requirement for nuclear signaling. The MAPK pathway is strongly implicated in mGluR-dependent LTD. (J) One newly synthesized protein that acts as a maintenance mechanism for late LTP is PKMζ. This remarkable kinase comprises the active subunit of PKM, an isoform of PKC, that is now known to maintain the presence of AMPA receptors inserted during LTP induction, and thereby maintain LTP. Inhibition of this kinase can erase LTP and memory many days after induction. (K) Finally, BDNF can also play a second role in synaptic plasticity, as a newly synthesized product that alters the structure of the synapse to enforce long-term changes in synaptic strength.