Figure 6

Schematic diagram illustrating the role of proteins encoded DEGs and DASGs and others on AMPA-receptor signaling and synaptic plasticity. mRNA expression of NSF-attachment protein alpha (Napa), pentraxin 1 (Nptx1, NP1), synaptotagmin 7 (Syt7), neurogranin (Nrgn, Ng), Slc8a2, and Camk2b was higher in the HP group (corresponding to the proteins highlighted in red). The HP group also has an increased flip/flop transcript ratio of subunits Glur1 and Glur2. The flip isoform renders AMPA receptors less prone to desensitization as compared to the flop isoform, but AMPA receptor affinity for glutamate remains unchanged^48,91. Fast, excitatory synaptic transmission in the brain is primarily mediated by two types of ionotropic glutamatergic receptors: AMPA and NMDA receptors. Calcium entry through postsynaptic NMDA receptors activates intracellular signaling cascades including calmodulin (CaM) and CaMK2 signaling. Ng concentrates CaM to participate in postsynaptic signaling processes^92,93. Ng phosphorylation by PKC disrupts its binding to CaM, thereby leading to the activation of the CaMK2β signaling pathway and induction of LTP. CaMK2β potentiates ion channel function of AMPA receptor via direct phosphorylation of AMPA receptor subunits⁹⁴. Another kinase, PKA, phosphorylates the C-terminal domain of AMPA receptor subunits and thus controls synaptic trafficking that underlies plasticity⁹⁵. Syt7 is essential specifically for Ca²⁺-induced AMPA receptor recruitment during LTP⁶⁰ and contributes to the rapid decrease of cytoplasmic Ca²⁺ levels back to baseline after neuronal activation, thereby contributing to the modulation of synaptic plasticity⁹⁶. NP1 drives the clustering of AMPA receptors at the postsynaptic membrane, promotes excitatory synaptogenesis, and mediates synaptic recruitment of AMPA receptor^55,56. Thus, phosphorylation of AMPA receptor mediated by CaMK2β as well as an increased level of Napa, Nptx1, and Syt7 and the increased flip/flop isoform ratio of GluR1 and GluR2 during LTP potentiate ion channel function, cause desensitization, and increase the levels of synaptic AMPA receptors.