A cell type-specific switch in GluN2D NMDA receptors drives cortical circuit hyperexcitability and sensory-driven cortical synchronization deficits in a Fragile X Syndrome model.

Background

Altered sensory processing and sensitivity are prevalent in Fragile X Syndrome (FXS) and may be mediated by dysfunction of cortical circuits. Evidence from individuals with FXS and/or the FXS mouse model, Fmr1 KO, indicates hyperexcitability of sensory cortical circuits, deficits in sensory-driven circuit synchrony and sensory-induced seizures. GluN2D-containing NMDA receptors (NMDARs) are enriched in cortical inhibitory neurons. We hypothesized that selective activation of GluN2D may correct cortical circuit hyperexcitability, seizures, and synchrony deficits in Fmr1 KO mice.

Methods

To test this hypothesis, we used pharmacology and cell type-specific genetic manipulation of GluN2D combined with multi-unit and single cell electrophysiology in cortical slices and multielectrode EEG in vivo to examine the functional contribution of GluN2D to cortical circuit dysfunction in the Fmr1 KO mouse.

Results

In contrast to our hypothesis, pharmacological inhibition of GluN2D-containing NMDARs corrects cortical circuit hyperexcitability, reduces sensory-driven seizures and improves EEG synchrony in Fmr1 KO mice. We demonstrate a switch in the cell type-specific functional expression of GluN2D-containing NMDARs in Fmr1 KO, from inhibitory to excitatory cortical neurons, which drives circuit hyperexcitability. In support of this conclusion, the mRNA for GluN2D (Grin2d) is upregulated in Fmr1 KO excitatory neurons and genetic reduction of Grin2d in excitatory neurons corrects measures of circuit hyperexcitability in Fmr1 KO mice.

Conclusions

Our results reveal an unexpected cell type-specific switch in GluN2D-containing NMDARs in a model of a major genetic cause of intellectual disability and autism and suggest a novel therapeutic strategy to aid sensory processing deficits in FXS.