Figure 2. Molecular mechanisms of NMDAR activation-dependent LTP.

Canonical NMDAR activation-dependent LTP induction is initiated by simultaneous AMPAR-mediated postsynaptic depolarization and glutamate binding to the NMDAR, facilitating NMDAR activation and Ca²⁺ influx after the release of an NMDAR Mg²⁺ block. LTP expression is instigated by Ca²⁺/calmodulin-dependent signaling that enables postsynaptic kinase activity (e.g., CaMKII, PKC) to promote enhanced synaptic transmission via numerous alterations including phosphorylation of glutamatergic receptors, trafficking of AMPARs to the postsynaptic membrane, and lateral diffusion of extrasynaptic AMPARs. Initiation of gene transcription is mediated by numerous signaling cascades (e.g., adenylyl cyclase-cAMP-PKA) and protein kinases (e.g., CaMKIV). LTP maintenance requires de novo protein synthesis either in the soma (e.g., CREB-dependent gene transcription and subsequent translation of proteins such as c-fos, Arc, AMPAR, NMDAR; BDNF-TrkB-mTORC1 also contribute) or translation of transcripts localized to dendrites, yielding long-lasting alterations in synaptic efficacy. Abbreviations: AC, adenylyl cyclase; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CaMKII, Ca²⁺-calmodulin-dependent protein kinase II; CaMKII, Ca²⁺-calmodulin-dependent protein kinase IV; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; LTP, long-term potentiation; mTORC1, mechanistic target of rapamycin complex 1; NMDAR, N-methyl-D-aspartate receptor; PKA, protein kinase A; PKC, protein kinase C; TrkB, tropomyosin receptor kinase B. Created with Biorender.com