A mouse model of GRIN2D developmental and epileptic encephalopathy recapitulates the human disease.
Brain : a journal of neurology – April 25, 2025
Source: PubMed
Summary
Scientists have uncovered vital insights into developmental epilepsy by studying a specific genetic mutation in GRIN2D, a crucial brain receptor component. Using an innovative mouse model, researchers revealed how this mutation triggers severe seizures and developmental issues that mirror human symptoms. Brain activity recordings (ECoG) showed distinctive abnormal patterns, while drug response testing found that memantine and phenytoin offered modest benefits, unlike ketamine which worsened symptoms.
Abstract
Pathogenic variants in GRIN2D, encoding one of the subunits of the NMDA receptor (NMDAR), are associated with developmental and epileptic encephalopathies (DEEs). Unusual for de novo mutations, the recurrent, de-novo, gain of function, missense mutation c.1999G>A (p.Val667Ile) was discovered in multiple patients. We characterized a mouse model carrying the orthologous Grin2d mutation, using behavioral paradigms, electrophysiological recordings in acute brain slices focusing mainly on the activity of Purkinje neurons (PNs) in the cerebellum, and electrocorticography (ECoG) recordings monitoring brain activity and the response to several drugs. Grin2d mutant mice exhibit a range of phenotypes that closely mirror the human disease, including premature mortality, spontaneous seizures, and early onset of motor deficits followed by cognitive impairment. In addition, we observed complex developmental changes in PNs with reduced spontaneous firing in immature mice and augmented synaptic response to NMDA application in older mice. ECoG recordings demonstrated profound and continuous abnormal brain activity, with altered spectral properties and a prominent narrowband activity in the theta, alpha, and beta bands, paralleling the patterns seen in a patient with the same GRIN2D pathogenic variant. Acute administration of ketamine at a low dose (0.5 mg/kg) had a limited effect on the spectral properties, and higher dosages (4 or 10 mg/kg) caused seizures. Conversely, memantine (10 mg/kg) and phenytoin (30 mg/kg) demonstrated a small corrective effect on ECoG properties. Together, Grin2d mutant mice recapitulate key phenotypes of patients with pathogenic GRIN2D variants, including unique, abnormal brain oscillations, which may serve as a biomarker for quantifying drug responses and guiding future research efforts.