Long-term potentiation (LTP) is the increase of synaptic strength between two neurons following high frequency stimulation to the synapse. A majority of synapses that experience LTP (e.g. in the hippocampus) involve a postsynaptic increase in calcium which is mediated through activation of the ionotropic glutamate receptor N-methyl-D-aspartic acid (NMDA) receptor. Activation of NMDA receptors by glutamate released from the presynaptic neuron results in Ca2+ influx which coactivates the extracellular regulated signal kinase (ERK) and cyclic adenosine monophosphate (cAMP) signal transduction pathways. Activation of these two regulatory pathways increases the transcription of a family of genes via the cAMP responsive element binding (CREB) protein activation. CREB mediated transcriptional activation in the post synaptic neuron is believed to be an important event in LTP.
The NMDA receptor mediated Ca2+ flux activates Calmodulin dependent adenylyl cyclases which play a critical role in generating the cAMP, which in turn activates protein kinase A (PKA). The activation of PKA plays a major role in supporting the nuclear translocation of ERK. ERK activation leads to indirect activation of CREB by coupling to ribosomal protein S6 kinase (RSK), which then phosphorylates and activates CREB. The activation of PKA also results in the activation of I-1, an inhibitor of protein phosphatase 1 (PP1). In the absence of activated I-1, calmodulin kinase II (CaMKII) is dephosphorylated and inactivated by PP1. The NMDA receptor dependent PKA mediated phosphorylation of I-1 thus results in the activation of CaMKII, one of the most abundant proteins in neurons. Activated CaMKII plays a role in the activation and phosphorylation of the ionotropic glutamate receptor alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor.This covalent modification of AMPA receptors results in a modulation of receptor numbers and therefore to an increased response to glutamate - an important postsynaptic event in LTP. The NMDA mediated Ca2+ flux also activates CaMKIV which triggers CREB/ CREB binding protein (CBP)-dependent transcription by phosphorylating CBP.
In addition to the ionotropic glutamate receptors, the metabotropic glutamate receptors mGluR also play a role in LTP. The mGluR via coupled G protein activates the phospholipase C (PLC)/protein kinase C (PKC) pathway which triggers the NMDA receptor, thus increasing Ca2+ influx. The inositol triphosphate (IP3) generated as a result of PLC activation increases Ca2+ release from intracellular sources, further activating calmodulin dependent pathways.
This pathway highlights the important components of Long term potentiation signaling.