N-methyl-D-aspartate receptor (NMDAR) hypofunction is a central pathophysiological mechanism in schizophrenia, yet direct NMDAR potentiation has shown limited clinical benefit, potentially because it fails to address deficits in receptor trafficking and surface stability. The endosomal sorting complexes required for transport (ESCRT) machinery governs the lysosomal fate of internalised membrane proteins, but its role in synaptic receptor homeostasis during glutamatergic dysfunction remains unclear. Phencyclidine (PCP), a non-competitive NMDAR antagonist, is widely used to model NMDAR hypofunction and schizophrenia-like phenotypes. Here, we show that sub-chronic PCP exposure induced persistent NMDAR hypofunction, impaired GABAergic transmission, and collapsed of excitation/inhibition (E/I) balance in primary hippocampal neurons. Genetic inhibition of the ESCRT-I component TSG101 prevented these deficits, enabled functional recovery following PCP washout, and increased surface expression of functional NMDARs and GABAA receptors without altering receptor pharmacology or biophysical properties. At the network level, TSG101 knockdown restored inhibitory tone, normalised excitatory activity, and stabilised E/I balance. Moreover, TSG101 knockdown rescued PCP-induced reductions in PSD-95 and BDNF, restored ERK1/2 signalling, and re-established activity-dependent nuclear translocation of Fos-like (Fos-L), consistent with reactivation of transcriptional plasticity. These findings identify ESCRT-I as a regulator of synaptic stability, positioning endosomal sorting pathways as a potential therapeutic target for schizophrenia.
Shalaby, M., Prato, V., Elies, J. G., Gamper, N., Mclean, S. L., Kantamneni, S.
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