NMDA current is enhanced by MβCD-induced D1-NMDA receptor perturbation in hippocampal CA1

Abstract

N-methyl-d-aspartate receptors (NMDARs) located in hippocampal CA1 are modulated by D1 receptors (D1Rs). This modulation is thought to be exerted by direct protein-protein interactions. Thus, the nearest spatial and temporal relationship amongst them, immersed in a lipid raft, seems critical in passing the signaling on to each other. However, whether this modulation is affected by disturbing lipid raft conformations is still unknown. Therefore, this work aimed to investigate changes in CA1 synaptic responses resulting from disrupting NMDARs-D1Rs interactions. Experiments were conducted on hippocampal slices obtained from 15-day-old Wistar rats. A selective D1Rs antagonist (SCH23390) was used to reduce NMDA current (NMDAc) activity, suggesting a potential influence of endogenous dopamine (DA). This finding was further supported by depleting DA in experiments including reserpine. Dopaminergic modulation of NMDAc was assessed in slices preincubated with Methyl-β-cyclodextrin (MβCD). Exposure to SCH23390 in MβCD-treated slices significantly enhanced amplitude and τ deactivation of NMDAc compared to slices treated with SCH23390 solely. These alterations were readily correlated with changes in synaptic efficacy. Moreover, CaMKII inhibitory peptide 281–309 significantly counteracted the increased synaptic response observed in SCH23390 + MβCD conditions_. Together, these results support the notion that lipid rafts perturbation impedes a NMDARs-D1Rs interaction, therefore a modulatory inhibition depending on this interaction.