FENS 2022 – Neurotransmission

Paris – France

Subcommissural organ-spondin-derived peptide (NX210c) promotes glutamatergic receptor-related synaptic transmission and signaling in the mouse CNS

Sighild Lemarchant¹, Mélissa Sourioux¹, Stéphanie Aguéro², Juliette Le Douce¹, Julie-Anne Chemelle², Sandrine Hugues³, Mélissa Farinelli³, Raphaël Terreux², Yann Godfrin^1,4

 ¹Axoltis Pharma, Lyon, France ²ECmo Team, Tissue Biology and Therapeutic Engineering Laboratory, UMR 5305 CNRS UCBL, Lyon, France ³E-Phy-Science, Bioparc, Sophia-Antipolis, Biot, France ⁴Godfrin Life-Sciences, Caluire-et-Cuire, France

Aim

NX210c is a disease-modifying dodecapeptide, derived from the subcommissural organ-spondin, under clinical development for the treatment of neurological disorders.  Here, we have evaluated the effect of NX210c on synaptic function/dysfunction.

Methods

NX210c (250 µg/mL) was superfused on mouse brain slices to measure (1) NMDAR- and AMPAR-mediated excitatory postsynaptic currents (EPSCs) at hippocampal CA3-CA1 synapses, and (2) extracellular field excitatory postsynaptic potentials (fEPSPs) recordings at hippocampal and thalamocortical synapses.

NX210c (5 mg/kg) was injected intraperitoneally in mice with cortical synaptic dysfunctions induced by chronic administrations of the NMDAR antagonist phencyclidine (PCP) to evaluate working memory (% of alternations in the T-maze) and GluN2A-NMDAR and phosphorylated CREB levels in cortical protein extracts (western-blot).

Results

NX210c increased EPSC amplitudes mediated by NMDAR (+79.2%, p=0.0469 vs baseline), more specifically GluN2A-NMDAR, and AMPAR (+16.7%, p=0.0191 vs baseline), as well as fEPSP slopes (p=0.0356 and p=0.0027 vs control for hippocampal and thalamocortical synapses), consistent with the in silico docking of NX210c to glutamatergic receptors. Accordingly, a single acute administration of NX210c in PCP-injected mice restored working memory (-35.7 and -13.5% of alternations for vehicle- and NX210c-treated PCP mice compared with control mice). Further, repeated daily administrations of the peptide induced a two-fold increase in GluN2A-NMDAR protein levels and reversed PCP-induced decrease in pCREB, which also restored memory (-4.3% of alternations for NX210c-treated PCP mice compared with control mice).

Conclusions

The action of NX210c on GluN2A-NMDAR and AMPAR represents an innovative therapeutic opportunity to ameliorate outcomes in patients suffering from CNS disorders with crippling synaptic dysfunctions.