David Soto1, Mireia Olivella2, Cristina Grau3, Judith Armstrong4, Clara Alcon5, Xavier Gasull1, Macarena Gómez de Salazar3, Esther Gratacòs-Batlle1, David Ramos-Vicente6, Víctor Fernández-Dueñas7, Francisco Ciruela7, Àlex Bayés6, Carlos Sindreu5, Anna López-Sala8, Àngels García-Cazorla9, Xavier Altafaj10. 1. Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Department of Biomedicine, University of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain. 2. Bioinfomatics and Medical Statistics Group, University of Vic-Central University of Catalonia, Barcelona, Spain. 3. Bellvitge Biomedical Research Institute-Unit of Neuropharmacology and Pain Group, University of Barcelona, Barcelona, Spain. 4. Genetics and Molecular Medicine Service, Hospital Sant Joan de Déu and Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain. 5. Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Department of Clinical Foundations, University of Barcelona, Barcelona, Spain. 6. Molecular Physiology of the Synapse Laboratory, Biomedical Research Institute Sant Pau, Barcelona, Spain; Autonomous University of Barcelona, Bellaterra, Barcelona, Spain. 7. Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Spain; Bellvitge Biomedical Research Institute-Unit of Neuropharmacology and Pain Group, University of Barcelona, Barcelona, Spain. 8. Department of Neurology, Neurometabolic Unit, Hospital Sant Joan de Déu and Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain. 9. Genetics and Molecular Medicine Service, Hospital Sant Joan de Déu and Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain; Department of Neurology, Neurometabolic Unit, Hospital Sant Joan de Déu and Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain. 10. Bellvitge Biomedical Research Institute-Unit of Neuropharmacology and Pain Group, University of Barcelona, Barcelona, Spain. Electronic address: xaltafaj@idibell.cat.
Abstract
BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B(p.P553T) coding for the GluN2B subunit of NMDAR. METHODS: We generated a dynamic molecular model of mutant GluN2B-containing NMDARs. We expressed the mutation in cell lines and primary cultures, and we evaluated the putative morphological, electrophysiological, and synaptic plasticity alterations. Finally, we evaluated D-serine administration as a therapeutic strategy and translated it to the clinical practice. RESULTS: Structural molecular modeling predicted a reduced pore size of mutant NMDARs. Electrophysiological recordings confirmed this prediction and also showed gating alterations, a reduced glutamate affinity associated with a strong decrease of NMDA-evoked currents. Moreover, GluN2B(P553T)-expressing neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of GluA1 at stimulated synapses. Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p.P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation. CONCLUSIONS: Our data suggest that hypofunctional NMDARs containing GluN2B(p.P553T) can contribute to Rett-like encephalopathy and that their potentiation by D-serine treatment may underlie the associated clinical improvement.
BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B(p.P553T) coding for the GluN2B subunit of NMDAR. METHODS: We generated a dynamic molecular model of mutant GluN2B-containing NMDARs. We expressed the mutation in cell lines and primary cultures, and we evaluated the putative morphological, electrophysiological, and synaptic plasticity alterations. Finally, we evaluated D-serine administration as a therapeutic strategy and translated it to the clinical practice. RESULTS: Structural molecular modeling predicted a reduced pore size of mutant NMDARs. Electrophysiological recordings confirmed this prediction and also showed gating alterations, a reduced glutamate affinity associated with a strong decrease of NMDA-evoked currents. Moreover, GluN2B(P553T)-expressing neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of GluA1 at stimulated synapses. Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p.P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation. CONCLUSIONS: Our data suggest that hypofunctional NMDARs containing GluN2B(p.P553T) can contribute to Rett-like encephalopathy and that their potentiation by D-serine treatment may underlie the associated clinical improvement.
Authors: Rosana Leiva; Matthew B Phillips; Andreea L Turcu; Esther Gratacòs-Batlle; Lara León-García; Francesc X Sureda; David Soto; Jon W Johnson; Santiago Vázquez Journal: ACS Chem Neurosci Date: 2018-06-01 Impact factor: 4.418
Authors: Paulina Kyriakopoulos; Vanda McNiven; Melissa T Carter; Peter Humphreys; David Dyment; Tadeu A Fantaneanu Journal: Child Neurol Open Date: 2018-08-23