Sleep and epilepsy phenotypes in rodent models of neurodevelopmental disorders

Abstract

Globally an estimated 2-5% of children and adults have neurodevelopmental disorders (NDDs), which include autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder. Genetic factors constitute a significant risk factor for NDDs, and genetic aetiologies underlie many of the more severe disorder cases. The rate of comorbidity between NDDs and epilepsy is high, with 20-30% of individuals with NDDs presenting with seizures, while sleep impairments are prevalent in an overwhelming 80% of NDD cases, further exacerbating cognitive deficits and the severity of epileptic activity. However, comprehensive long-term quantitative data on sleep and circadian disruptions in individuals with NDDs, especially in those with rare genetic disorders, is scarce, hindering the development of targeted novel therapeutic interventions. Moreover, epilepsy and NDDs result from disruptions in brain circuit formation and aberrant neuronal signalling and activity, although our understanding of the precise pathophysiological mechanisms associated with specific genetic mutations underlying NDDs remains limited.

Using EEG and pharmacological experiments, this thesis investigates and quantifies dysfunctional sleep and seizure activity in three rodent models of genetic NDDs and epilepsy: namely in rat lines of Grin2b haploinsufficiency (Grin2b+/-), Nlgn3 disorder (Nlgn3-/y), and 16p11.2 deletion syndrome (16p11.2+/-). Altered sleep physiology dynamics were observed in Nlgn3-/y rats, while an unexpected male-specific increase in rapid eye movement (REM) sleep was found in 16p11.2+/- animals. Grin2b+/- rats displayed REM sleep deficits and altered sleep physiology alongside an absence seizure phenotype. Grin2b+/- animals presented with spike and wave discharges in their EEG, a hallmark characteristic of absence epilepsy that correlates with seizures, thought to occur due to abnormal thalamocortical signalling. These seizures were blocked with systemic pharmacological interventions, which was replicated by drug application specifically to the reticular thalamic nucleus, suggesting an impairment of thalamocortical network activity in Grin2b+/- rats. Overall, findings from this thesis are consistent with clinical observations of dysfunctional sleep in NDDs and provide quantifiable evidence for specific sleep abnormalities in rare GRIN2B, NLGN3 and 16p11.2 related disorder animal models. Furthermore, I report the presence of spontaneous absence seizures in a novel rat model of GRIN2B haploinsufficiency that are sensitive to pharmacological treatment. The sleep and seizure phenotypes, along with pharmacological findings from this thesis, may have translational utility if extended to the clinical setting.