Preclinical models of developmental and epileptic encephalopathies (DEEs) are essential tools for uncovering disease mechanisms and identifying objective biomarkers that extend beyond convulsive seizure activity. Our research utilizes three complementary mouse models: SCN1A (Dravet syndrome), GRIN2D-DEE, and CHD2-DEE.
Mouse models of Dravet syndrome (DS) recapitulate the severe epilepsy, motor impairments, and cognitive deficits observed in patients. While correction of these phenotypes and protection from premature mortality are commonly used to assess therapeutic efficacy, their high variability limits quantitative comparisons between treatments and reduces sensitivity in detecting partial rescue.
Using DS mice harboring the missense Scn1aA1783V mutation, we identified electrographic biomarkers based on background power spectral density (PSD), sleep architecture, and thermoregulation that are independent of convulsive seizure burden. Electrocorticographic (ECoG) analysis revealed a marked global reduction in PSD in DS mice. Furthermore, we discovered disrupted temperature-sleep coupling: unlike wild-type mice, DS mice fail to decrease core body temperature at NREM sleep onset and show diminished delta power increases during wake-to-sleep transitions. Additionally, warmth-induced somnogenesis is impaired, as elevated ambient temperatures fail to promote sleep in DS mice. Remarkably, canine adenovirus type 2 (CAV2)-mediated gene therapy delivering a codon-optimized SCN1A transgene restored background PSD, the sleep-related delta ratio, and warmth-induced somnogenesis.
Similar PSD reductions were observed in a mouse model of CHD2-DEE harboring a frameshift mutation. These mice exhibit motor deficits and autism-like behaviors, alongside a global reduction in background oscillatory power and decreased interhemispheric coherence, resembling the electrographic alterations in DS mice.
Finally, in a GRIN2D-DEE mouse model carrying the recurrent V667I gain-of-function mutation, which exhibits profound mortality, motor and cognitive deficits, we identified exceptionally sustained and continuous abnormal brain activity. ECoG recordings revealed a distinctive spectral signature characterized by prominent narrowband activity in the theta, alpha, and beta bands, closely paralleling the EEG patterns observed in human patients with the same variant.
These studies demonstrate that DEE models share core non-seizure comorbidities, including motor impairments and cognitive deficits, as well as quantitative alterations in background brain oscillations. These electrographic features provide more sensitive and objective biomarkers than seizure frequency alone for tracking disease progression and evaluating therapeutic responses.