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.