Developmental epileptic encephalopathies (DEEs) are a wide group of neurodevelopmental disorders. One of the genes related is the GRIN2D gene, which encodes for one of the subunits of the N-Methyl-D-Aspartate receptor (NMDAR).

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Functional evaluation of this mutation in vitro demonstrated a gain-of-
function effect. Yet patients' response to NMDAR antagonists is variable, indicating that the effect of this mutation on brain function may be more complex.

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In this research proposal, we aim to characterize the neuronal and synaptic alterations in Grin2d mice, utilizing cerebellum brain slices. Focusing on the activity of Purkinje cells we found reduced frequency and lower amplitude of spontaneous postsynaptic potentials (sPSPs) in Grin2d mice.

 

These sPSPs were completely abolished in the presence of the GABAAR antagonist
Picrotoxin indicating that these are mainly inhibitory inputs. Interestingly, the addition of NMDA increased these sPSPs, with a tendency for a stronger effect in the Grin2d mice.

 

Together, these results indicate that although the mutation directly affects the NMDAR, it may also alter the activity of other ion channels. To further examine the effect of the mutation on the cerebellar circuitry, we will perform electrophysiology recordings to explore changes in the firing properties and excitability of Purkinje cells in wild-type and Grin2d mice.

 

Finding differences in the circuit activity in Grin2d mutant mice will promote our understanding of the neuronal mechanism of the disease and Grin2d containing NMDARs in this circuit.