N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ligand-gated cation channels that function as excitatory glutamatergic neurotransmitter receptors important in synaptic plasticity. GRIN2D is a component of a subset of NMDARs that is broadly expressed in the brain during embryonic development and in the adult is found in the diencephalon, brainstem, cerebellum, spinal cord, cortex and hippocampus. This conditional allele, which after cre recombination results in a 2 base pair mutation that causes a V664I amino acid substitution in the M3 transmembrane domain, is orthologous to the human V667I dominant gain of function mutation found in some cases of severe developmental and epileptic encephalopathy 46 (MIM:617162). The M3 transmembrane domain is involved in channel gaiting and this gain-of-function mutation increases open channel probability, increases glutamate and glycine potency, and prolongs the deactivation time course after glutamate removal. Mice constitutively heterozygous for this substitution (Grid2dem9Frk) have normal Mendelian inheritance and survival through early development, but adults have frequent spike-wave discharges that often last for minutes, and lethal convulsive seizures have been observed as early as 17 days of age. Approximately half of the Grid2dem9Frk heterozygotes die by 3 weeks of age and few survive beyond 45 days of age. Those heterozygous V664I pups emit more ultrasonic vocalization calls from maternal separation than is normal, have delayed growth as assessed by body weight as early as 4 days of age, which persists, and display abnormal hindlimb clasping at 2 weeks of age. Although the brains are of normal length, hypoplasia of the thalamus, hypothalamus, striatum, and cerebellum are found at both 7 and 14 days of age in Grid2dem9Frk heterozygotes. Synaptic density in neurons is decreased and presynaptic termini are enlarged. CA1 inhibitory neurons have a prolonged decay time constant and the hippocampal local field potentials have increased evoked responses and action potential generation. This conditional-ready allele, Grid2dem10Frk, expresses the wildtype Grin2d sequence and is viable and fertile in both the heterozygous and homozygous state. This floxed allele allows localized inducible expression of the V664I mutation. After Cre-recombination through breeding to Edil3Tg(Sox2-cre)1Amc, 64% of the resultant Grid2dem10.1Frk gain of function V664I heterozygotes were still alive at 31 days of age. Multiple seizure types were recorded by video electroencephalography of the Sox2-cre V664I heterozygotes, all of which showed spike-wave discharges at all ages assessed, some lasting minutes, and some had lethal clonic-tonic seizures. Epileptic bursts were found as early as 13 days of age. This conditional-ready allele allowed Teoh et al. to breed it to more restricted neuronal cre drivers to delineate the impact on distinct neuronal subtypes. (Teoh et al., 2025)

The use of this mouse model is subject to the terms and conditions of the Limited Use Label License from Caribou Biosciences, Inc.

The use of this mouse strain or other product (the "Licensed Product") is subject to the terms and conditions of the Limited License from The Broad Institute.

This conditional allele, which after Cre recombination results in a 2 base pair mutation that causes a V664I amino acid substitution in the M3 transmembrane domain, is orthologous to the human V667I dominant gain of function mutation found in some cases of severe developmental and epileptic encephalopathy 46 (MIM:617162).

Typically mice are recovered in 12-16 weeks. Contact Customer Service to place an order or for more information.

<a target="_blank" href="https://www.jax.org/jax-mice-and-services/customer-support" rel="noreferrer">Contact Customer Service</a> for more information.