NMDAR glycine-site activation differentially modulates intrinsic properties of intratelencephalic and pyramidal-tract neuron via distinct ionic mechanisms

The glycine binding site of N-methyl-d-aspartate receptors (NMDARs) has emerged as a critical target for cognitive dysfunction in schizophrenia, yet repeated clinical failures reveal incomplete understanding of its modulation. In the present study, we investigated how glycine site activation affects neuronal intrinsic properties in different types of prefrontal pyramidal neurons, which were classified as intratelencephalic (IT) and pyramidal-tract (PT) neurons based on unsupervised clustering of membrane properties. We found that d-serine, a co-agonist of NMDAR glycine site, produced distinct effects across neuron subtypes. d-serine reduced firing rate in IT neurons by recruiting small conductance Ca²⁺-activated K⁺ (SK) channels. In contrast, d-serine selectively altered firing pattern of PT neurons by slowing kinetics of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Transcriptomic analysis revealed cell-type-specific expression patterns of regulatory proteins associated with these channels. Subsequent functional validation demonstrated that SK channel recruitment in IT neurons requires L-type Ca²⁺ channels and CaMKII activation. These findings provide new insight into the cell-type-specific modulatory roles of NMDAR glycine-site activation beyond conventional excitatory signaling.