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. 2023 Oct 26;17:1267647. doi: 10.3389/fnins.2023.1267647

FIGURE 2.

FIGURE 2

Potential neuroplastic mechanisms underlying the therapeutic and synergistic effects of combined rTMS and ketamine treatment: rTMS and ketamine induce glutamate release, which at a molecular level causes NMDAR and AMPAR activation through signaling pathways, including CaMKII, PKC, PKA, BDNF/TrkB, MAPK, and mTOR. The CaMKII and PKC pathways, as well as the TrkB pathway, stimulate AMPAR trafficking into the postsynaptic neuron membrane, which is one of the mechanisms of E-LTP. PKA, BDNF/TrkB, MAPK, and mTOR pathway activation induces modulation of plasticity-related gene transcription and protein synthesis. These processes underlie L-LTP development. The expression of genes that are essential for synaptic plasticity may also be stimulated by dopamine activation of D1R, D3R, or both, through PKA and MAPK pathways. This intracellular process results in synaptogenesis, synaptic modulation, and dendritic growth, leading to connectivity changes in the PFC, hippocampus, limbic cortex, and DMN. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF, brain-derived neurotrophic factor; CaMKII, Ca2+/calmodulin-dependent protein kinase; D1/D5R, dopamine receptor 1/5; DMN, default mode network; E-LTP, early long-term potentiation; L-LTP, late long-term potentiation; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NMDAR, N-methyl-D-aspartate receptor; PFC, prefrontal cortex; PKA, protein kinase A; PKC, protein kinase C; TrkB, tropomyosin receptor kinase B.