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Grin1 knockdown mice (Grin1KD) have a loss-of-function mutation that is caused by the insertion of foreign DNA into an intron of the Grin1 gene. Although this mouse does not model a
specific patient variant, it is a useful model to understand how brain functions are altered by a global reduction of NMDA receptors. Grin1KD mice display many phenotypes that are similar to patient symptoms, including increased motor activity, decreased muscle tone, increased stereotypic movements,
and impairments in multiple domains of cognition. We asked whether phenotypes of Grin1KD mice could be improved by genetic rescue of the knockdown mutation in adult mice. To do this, we used a tamoxifen inducible Cre recombinase to excise the mutation and restore the Grin1 gene to a wildtype configuration. We discovered that several forms of cognition were improved or even normalized when genetic rescue was performed in adult mice. Our results suggest that the adult brain has sufficient plasticity to overcome developmental insults to NMDA receptor function, which has important implications for patients with GRIN disorders.
While gene therapy may be possible in the future, there are a number of pharmacological interventions that can be tested in this model and quickly translated to patients. As an example, we
tested the ability of a ketogenic diet or dietary ketone ester to improve behavioural phenotypes of Grin1KD mice. We discovered that either the ketogenic diet or beta-hydroxybutyrate improved the Grin1KD phenotypes of hyperactivity, sociability, sensory processing, and spatial memory. Similar studies could be used to test novel pharmacological agents that increase NMDA receptor activity.