Figure 1. LTP and LTD as two forms of hippocampal synaptic plasticity in PSD disease.
Figure 2. Schematic diagram of the pathways involved in BDNF regulation of hippocampal synaptic plasticity. Pro-BDNF binds to sortilin with relatively high affinity and promotes LTD. Pro-BDNF is converted to mature BDNF and binds to hippocampal postsynaptic TrkB to induce its autophosphorylation. The BDNF–TrkB complex enters the cell body and activates different signaling pathways to induce postsynaptic responses. These include the activation of PLCγ1-, PI3K-, and Ras-related pathways, which together activate intracellular CREB phosphorylation, induce its gene transcription in the nucleus, and promote neuronal survival. In addition, the postsynaptic BDNF–TrkB complex induces NMDAR phosphorylation, promotes Ca2+influx, and activates CaMKII to induce postsynaptic AMPAR phosphorylation. This promotes an increase in postsynaptic glutamate release and postsynaptic currents, facilitating LTP as a form of hippocampal synaptic plasticity.
Figure 3. CaMKII phosphorylation mediates two forms of glutamate receptor regulation involved in synaptic plasticity. a. At the postsynaptic membrane, Ca2+ influx activates CaMKII Thr286 phosphorylation, which not only promotes AMPAR Ser831 phosphorylation, but also promotes AMPAR binding to the phosphorylated protein stargazin, induces stargazin binding to PSD-95, increasing the number of AMPARs at the postsynapse, enhancing glutamate transmission, and promoting hippocampal LTP. In addition, CaMKII phosphorylation can also promote GluN2B binding to the corresponding protein and maintain LTP. b. Presynaptic inhibitory GABA receptors control Ca2+ influx. When NMDAR-mediated Ca2+ influx is attenuated, CaMKII Thr286 phosphorylation activates AMPAR at Ser567, which is involved in inhibiting synaptic enhancement and blocking Ser831 activation. CaMKII phosphorylation also promotes GABA receptor activation, which is involved in LTD.
Figure 4. Hippocampal Cx43 gap-junction channels regulate synaptic plasticity. Ca2+ waves in hippocampal astrocytes activate glutamate and ATP release into the synaptic gap through Cx43 gap-linked channels to promote neurogenesis. Glutamate release activates postsynaptic AMPARs and NMDARs to induce K+ efflux, and Cx43 gap-junction channels couple to take up extracellular K+ and glutamate and redistribute them to enhance LTP, while Cx43 gap linker protein reduces astrocyte volume, increases glutamate and K+spillover, and inhibits LTP. Another form of Cx43 hemichannels can release neurotransmitters and ATP involved in glutamatergic excitatory synaptic transmission, thereby inducing LTP.
Figure 5. Neurotransmitter-associated receptors regulate hippocampal synaptic plasticity. In the left panel, 5-HT activation of 5-HT7R and 5-HT2CR induces the onset of LTD, and the decrease in BDNF–TrkB signaling induces an increase in 5-HT2AR receptor activity which in turn induces LTD. Regarding DA neurotransmission, the D2-like receptor subtype D4R leads to a decrease in Ca2+influx through AMPARs, resulting in a decrease in CaMKII activity involved in the onset of LTD. In the right panel, both 5-HT- and DA-related receptors enhance excitatory transmission at hippocampal synapses via CREB-related pathways.