ESCRT-I Inhibition Protects against NMDAR Hypofunction and Restores Synaptic Homeostasis in a Cellular Model of Schizophrenia

Schizophrenia's underlying cause is N-methyl-D-aspartate receptor (NMDAR) hypofunction, but direct NMDAR enhancement has not yielded significant clinical improvements due to the receptor's issues with trafficking and surface stability. Researchers explored the role of the endosomal sorting complexes required for transport (ESCRT) machinery, which manages the lysosomal fate of internalized membrane proteins, in synaptic receptor homeostasis during glutamatergic dysfunction.

Using phencyclidine (PCP), a non-competitive NMDAR antagonist, as a model for NMDAR hypofunction and schizophrenia-like symptoms, they discovered that PCP exposure resulted in persistent NMDAR hypofunction, disrupted GABAergic transmission, and disrupted excitation/inhibition (E/I) balance in primary hippocampal neurons. By genetically inhibiting ESCRT-I component TSG101, they were able to counteract these deficits, enable functional recovery after PCP withdrawal, and elevate surface expressions of functional NMDARs and GABAA receptors without altering receptor pharmacology or biophysical characteristics.

At the network level, TSG101 knockdown restored inhibitory tone, normalized excitatory activity, and stabilized E/I balance. The study further revealed that TSG101 knockdown alleviated PCP-induced declines in PSD-95 and BDNF, restored ERK1/2 signaling, and re-established activity-dependent nuclear translocation of Fos-like (Fos-L), suggesting a reactivation of transcriptional plasticity.

These findings establish ESCRT-I as a regulator of synaptic stability, suggesting that endosomal sorting pathways could serve as a potential therapeutic target for schizophrenia.