NMDA receptor and its dependent synaptic plasticity
NMDA receptors are known to contribute to synaptic LTP (Bliss & Collingridge, 1993). In the ACC, there are two key forms of LTP: pre-LTP and post-LTP. For post-LTP, NMDA receptors, including GluN1 and GluN2 (GluN2A-D) isoforms, have been reported to contribute to the induction of LTP (Bliss et al. , 2016; Li et al. , 2019). LTP induction protocols such as theta burst stimulation (TBS), pairing training and spike-EPSPs can induce NMDA receptor-dependent LTP. The expression of NMDA receptor-dependent LTP requires postsynaptic modification or insertion of GluA1-containing AMPA receptors. AC1-dependent, protein kinase A (PKA) phosphorylation of AMPA receptors GluA1 contributes to LTP (Liauw et al. , 2005; Yamanaka et al. , 2017; Miao et al. , 2019). A recent study using selective knock-in mice demonstrates that phosphorylation of AMPA receptor GluA1 plays an important role in synaptic potentiation. However, the same LTP did not require CaMKII/PKC phosphorylation site serine 831 (Ser831). These results demonstrate that ACC LTP employs a different mechanism than hippocampal LTP (Song et al. , 2017).
In addition to post-LTP, an NMDA receptor-independent form of LTP can also be readily induced in the ACC by paired-pulse low-frequency stimulation. This form of LTP is resistant to NMDA receptor blockade and was inhibited in mice lacking the KA receptor GluK1 subunit (Kogaet al. , 2015). Pharmacological experiments using a potent GluK1-selective KA receptor antagonist, UBP310, further confirmed that this form of LTP is KA receptor-dependent. Both genetic and pharmacological evidence consistently indicates that this form of LTP is pre-LTP. Pre-LTP in the ACC is sensitive to a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, ZD7288 (Koga et al. , 2015). In addition, p42/p44 mitogen-activated protein kinase inhibitors PD98059 and U0126 suppressed the induction of pre-LTP and did not affect the maintenance of pre-LTP. The activation of presynaptic extracellular signal-regulated kinase was required for the induction of pre-LTP (Yamanaka et al. , 2016).