Neuroplastin Suppresses Seizures by Downregulating Endophilin A1 to Promote Internalization of GluA1-AMPA Receptors: Therapeutic Implications of Arbutin.

Status epilepticus (SE) is a critical neurological disorder characterized by an imbalance between excitatory and inhibitory neurotransmission. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate fast excitatory synaptic transmission, whereas internalization of GluA1-containing AMPARs regulates neuronal excitability. Although neuroplastin (Np) modulates neuronal excitability, its role in GluA1-AMPAR internalization in epilepsy remains unclear. Using single-cell transcriptomics, virtual knockout, in vitro and in vivo epilepsy models, patch-clamp, biochemistry, and behavioral tests, we identified Endophilin A1 (EndoA1) as a key target through which Np regulates GluA1 internalization. In epilepsy models, EndoA1 was upregulated, surface GluA1 levels increased, and receptor internalization was reduced. EndoA1 knockdown decreased the amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs), promoted GluA1 internalization, prolonged seizure latency, and shortened seizure duration. Np overexpression reduced EndoA1 expression, facilitated GluA1 internalization, and suppressed hyperexcitability, whereas EndoA1 knockdown rescued the Np knockdown-induced phenotype. Network pharmacology and molecular docking studies identified arbutin as an EndoA1-targeting compound that reduced hyperexcitability, mEPSC amplitude, and surface GluA1 in a concentration-dependent manner. These findings establish the Np-EndoA1-GluA1 axis as a key epileptic pathway, whereby Np negatively regulates EndoA1 to promote GluA1-AMPAR internalization and suppress excitability. Arbutin, which targets EndoA1, exerts anti-epileptic effects by modulating excitatory transmission.