Synaptic dysregulation in a mouse model of GRIN2D developmental and epileptic encephalopathy
Gain-of-function (GoF) variants in the GRIN2D gene, encoding the GluN2D subunit of the N-methyl-D-aspartate receptor (NMDAR), cause a severe developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, hypotonia and neurodevelopmental delay. We generated mice carrying the GoF V664I variant, orthologous to V667I, which is present in ∼25% of GRIN2D-DEE patients. Heterozygous mutant mice demonstrate behavioural, neuroanatomical and electrophysiological abnormalities. Lethal convulsive seizures are observed beginning at postnatal Day 17. As adults, heterozygotes display abundant and prolonged runs of spike-wave discharges (SWD) that often persist for minutes. The SWD epochs consist of different populations, differentiated by frequency and association with time-locked behavioural arrest. V664I mutant neurons have enlarged presynaptic terminals and increased synaptic distance. Functional analysis reveals increased inhibitory synaptic activity without changes in NMDAR decay kinetics or presynaptic plasticity in CA1 neurons, and analysis of hippocampal local field potentials shows a 1.5-fold increase in evoked responses and a 1.7-fold increase in action potential generation. Notably, expression of V664I in GABAergic interneurons, but not excitatory forebrain neurons, is sufficient to recapitulate the severe electroclinical phenotype. Altogether, our studies show that altered NMDAR function in inhibitory neurons plays a prominent role in DEE associated with GRIN2D GoF variants, suggesting that targeted genetic treatment may represent a path forward to successful therapeutic intervention.
Authors
- Chad R. Camp (ORCID: https://orcid.org/0000-0002-3415-4652)
- Christopher D. Makinson (ORCID: https://orcid.org/0000-0002-1427-8148)
- Sabrina Petri
- Moran Rubinstein (ORCID: https://orcid.org/0000-0003-2617-2276)
- Jennifer N. Gelinas (ORCID: https://orcid.org/0000-0002-1164-638X)
- Francesca Bartolini (ORCID: https://orcid.org/0000-0003-1048-622X)
- Jane Simko (ORCID: https://orcid.org/0000-0002-3632-4176)
- Caryn Martin
- Ayla Kanber
- Tristan T. Sands (ORCID: https://orcid.org/0000-0001-7285-1195)
- Cathleen M. Lutz (ORCID: https://orcid.org/0000-0003-2502-1900)
- Stephen F. Traynelis (ORCID: https://orcid.org/0000-0002-3750-9615)
- Noah D. Taylor
- Liang Ma (ORCID: https://orcid.org/0000-0003-3883-1902)
- Wanqi Wang (ORCID: https://orcid.org/0000-0001-7424-9165)
- Damian J. Williams (ORCID: https://orcid.org/0000-0001-5891-6300)
- Christine J. Liu
- Scott Q. Harper (ORCID: https://orcid.org/0000-0001-5135-4317)
- Jia Jie Teoh (ORCID: https://orcid.org/0000-0001-7100-5763)
- Moran Hausman‐Kedem (ORCID: https://orcid.org/0000-0001-5315-3738)
- Maria Elena Pero (ORCID: https://orcid.org/0000-0001-7262-6350)
- Aamir R. Zuberi (ORCID: https://orcid.org/0000-0003-0252-9760)
- Theresa C. Swayne (ORCID: https://orcid.org/0000-0002-1745-9753)
- Hongjie Yuan (ORCID: https://orcid.org/0000-0002-8127-7145)
- Divyalakshmi Soundararajan
- Wayne N. Frankel
- Ekniel François
- Aishwarya Ravichandra
Institutions
- Nationwide Children's Hospital (US)
- Emory University (US)
- Tel Aviv University (IL)
- Columbia University Irving Medical Center (US)
- Tel Aviv Sourasky Medical Center (IL)
- German Center for Neurodegenerative Diseases (DE)
- Institute for Neurodegenerative Disorders (US)
- Jackson Laboratory (US)
- The Ohio State University (US)
- Smith-Kettlewell Eye Research Institute (US)
- University of Naples Federico II (IT)
- Columbia University (US)
Publication Details
- Journal
- Brain
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1093/brain/awaf125
- Citations
- 4
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 3.64