Fig. 2

Long-term potentiation (LTP) induction. In basal “control” condition, glutamate (Glu) released by the pre-synaptic terminal after an electric stimulation interacts with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor, resulting in sodium (Na⁺) influx and an excitatory post-synaptic potential (control EPSP). In this condition, glutamate interaction with N-methyl-D-aspartate (NMDA) glutamate receptors has no consequence because of the voltage-dependent blockage by magnesium (Mg²⁺) of these receptors. During repetitive synaptic stimulation, which is mimicked in experimental conditions by the high frequency stimulation (HFS) protocol, the voltage-dependent NMDA blockage by Mg²⁺ is removed, allowing a Ca²⁺ influx into the post-synaptic element. This influx leads to the activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and other several kinases, not shown in the figure, such as protein kinase A (PKA), atypical protein kinase C isoforms and mitogen-activated protein kinases (MAPK), which induce molecular changes in the post-synaptic dendritic spine [1, 40]. AMPA receptors are phosphorylated with an increase in Na⁺ conductance, and more AMPA receptors are delivered to the plasma membrane from the sub-synaptic compartments. Moreover, neuronal gene expression is modulated in order to modify the morphology and the molecular structure of the dendritic spine. Finally, retrograde messengers like nitric oxide (NO), seem to play a role in LTP induction and maintenance, enhancing Glu release from the pre-synaptic element. All these synaptic modifications ultimately result in a sustained long-term increase of the EPSP (LTP), enhancing excitatory transmission between the two neurons