Clinical and therapeutic significance of genetic variation in the GRIN gene family encoding NMDARs

Abstract

Considerable genetic variation of N-methyl-d-aspartate receptors (NMDARs) has recently become apparent, with many hundreds of de novo variants identified through widely available clinical genetic testing. Individuals with GRIN variants present with neurological conditions such as epilepsy, autism, intellectual disability (ID), movement disorders, schizophrenia and behavioral disorders. Determination of the functional consequence of genetic variation for NMDARs should lead to precision therapeutics. Furthermore, genetic animal models harboring human variants have the potential to reveal mechanisms that are shared among different neurological conditions, providing strategies that may allow treatment of individuals who are refractory to therapy. Preclinical studies in animal models and small open label trials in humans support this idea. However, additional functional data for variants and animal models corresponding to multiple individuals with the same genotype are needed to validate this approach and to lead to thoughtfully designed, randomized, placebo-controlled clinical trials, which could provide data in order to determine safety and efficacy of potential precision therapeutics.

Keywords: Epilepsy; GRIN; Intellectual disability; NMDARs.

Figure 1.. GRIN variants are associated with various neurologic disorders.

A), Architecture and domain organization for the NMDAR. B), Summary of NMDAR variants in different GRIN subunits and domains. C), Summary of GRIN variant-associated phenotypes. ATD: amino terminal domain, ABD: agonist binding domain, TMD-link: transmembrane domains (M1-4) and linker regions, CTD: intracellular carboxy-terminal domain. ASD: Autism Spectrum Disorder, CVI: cortical visual impairment, Epi: epilepsy/seizures, Hypo: hypotonia, ID/DD: intellectual disability/developmental delay; LP/SP: language/speech problems; MD: movement disorders; Sleep: sleep problems. Many individuals showed multiple phenotypes, which are only a snapshot of the current literature, which is disproportionally weighted by different diagnostic approaches and ascertainment.

Fig. 2.. Mouse models of human GRIN variants.

A), Fluoro-Jade C staining showed that neurons of Grin1-KD mice in the striatum surrounding the anterior commissure are degenerating in the adult brain. B), Survival curve showing the rate and onset between postnatal days 15 and 17 of Grin2ap. S644G genotype-dependent in F2 hybrid male and female mice. C), Heterozygous (het) Grin2a-p.S644G adult mice have lower seizure threshold in minimal seizure end points. D), Hypoactivity in Grin2b^+/C456Y mice (P68–78) in the open-field test. E), Anxiolytic-like behavior in Grin2b^+/C456Y mice (P70–124) in the elevated plus-maze, as shown by entries into in closed arms. Modified with permission from (Intson et al., 2019) (A), (Amador et al., 2020) (B,C), and (Shin et al., 2020) (D,E).

Figure 3.. Therapeutic strategies for the treatment of GRIN variants.

A), Grin1 mRNA expression in Vglut+ cells in the adult mouse somatosensory cortex (1.53 mm lateral from midline). Grin1 (orange) and Vglut1 (green) mRNA was visualized in mouse sagittal sections (20 μm) with fluorescent in situ hybridization in WT, Grin1KD, and Grin1RESCUE mice. B), Impact of drug therapy on clinical seizures for the individual with GRIN2A-p.S644G variant. C), Pharmacological rescue of lethal seizures of p.S644G/p.S644G homozygotes, showing the respective survival after daily injections of dextromethorphan, quinidine, radiprodil, and Nuedexta®. D), Early chronic oral D-cycloserine (DCS) treatment (40 mg/kg) normalizes LFS-LTD at SC-CA1 synapses in juvenile Grin2b^+/C456Y mice (P17–20). E), Early chronic oral DCS treatment (40 mg/kg) improves anxiolytic-like behavior in adult Grin2b^+/C456Y mice (P63–73). Modified with permission from[77] (A), [58](B,C), and [59](D,E).