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bioRxiv · 10.1101/2024.12.15.628559

Non-ionotropic signaling through the NMDA receptor GluN2B carboxy terminal domain drives morphological plasticity of dendritic spines and reverses fragile X phenotypes in mouse hippocampus

Barnes, S. A.·Thomazeau, A.·Finnie, P. S. B.·Heinrich, M. J.·Heynen, A. J.·Komiyama, N.·Grant, S. G. N.·Menniti, F. S.·Osterweil, E. K.·Bear, M. F.
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Abstract

It is well known that activation of NMDA receptors can trigger long-term synaptic depression (LTD) and that a morphological correlate of this functional plasticity is spine retraction and elimination. Recent studies have led to the surprising conclusion that NMDA-induced spine shrinkage proceeds independently of ion flux and requires the initiation of de novo protein synthesis, highlighting an unappreciated contribution of mRNA translation to non-ionotropic NMDAR signaling. Here we used NMDA-induced spine shrinkage in slices of mouse hippocampus as a readout to investigate this novel modality of synaptic transmission. By using selective pharmacological and genetic tools, we find that structural plasticity is dependent on the ligand binding domain (LBD) of GluN2B-containing NMDA receptors and that metabotropic signaling occurs via the GluN2B carboxyterminal domain (CTD). Disruption of signaling by replacing the GluN2B CTD with the GluN2A CTD leads to increased spine density, dysregulated basal protein synthesis, and epileptiform activity in area CA3 reminiscent of phenotypes observed in the Fmr1-/y model of fragile X syndrome. By crossing the Fmr1-/y mice with animals in which the GluN2A CTD has been replaced with the GluN2B CTD, we observe a correction of these core fragile X phenotypes. These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for treatment of fragile X and related causes of intellectual disability and autism.

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Barnes, S. A., Thomazeau, A., Finnie, P. S. B., Heinrich, M. J., Heynen, A. J., Komiyama, N., Grant, S. G. N., Menniti, F. S., Osterweil, E. K., Bear, M. F.. 2024-12-16. Non-ionotropic signaling through the NMDA receptor GluN2B carboxy terminal domain drives morphological plasticity of dendritic spines and reverses fragile X phenotypes in mouse hippocampus. https://doi.org/10.1101/2024.12.15.628559

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