Fig. 5: Schematic illustrating proposed mechanism linking synaptic alterations to functional network reorganization and dynamics under GluN1-Ab.

We propose two concurrent processes drive the observed circuitopathy: (Left) Augmented NMDAR-dependent LTD (Fig. 3K) preferentially filters out weaker functional connections. This selective pruning leads to a sparser connectivity landscape (reduced overall functional connectivity; Fig. 3A, Supplementary Fig. 4A) and the partitioning of network organization into more numerous ensembles (Fig. 3G–I). Crucially, this removal of relatively weaker links increases the relative prominence of remaining local structures and stronger nodes, thereby contributing to higher functional clustering (Fig. 3F) and relative network hubness (Fig. 3D,E). (Right) Simultaneously, the selective maintenance of stronger excitatory synapses (supported by Fig. 3J) provides a backbone for presence of strong functional coupling between specific putative neuron (PN) pairs (Fig. 2). In the resulting sparser connectivity landscape (see Left), this maintenance manifests as relatively higher coupling (Fig. 2), network hubness (Fig. 3D,E), and intra-ensemble coupling (Fig. 4I). (Synthesis) The proposed interplay of these processes drives the GluN1-Ab-induced functional network rewiring observed in vivo, resulting in higher network synchrony (Fig. 1), inter-neuronal transmission fidelity (Fig. 4A–C,K), and similarity of spatiotemporal activity patterns (Fig. 4D–H). These profound alterations may contribute to the psychiatric and cognitive symptoms in NMDAR-Ab encephalitis (see Discussion). The mouse graphic was created in BioRender; Geis, C. https://BioRender.com/9qs1fwa (2026).