Investigating seizure manifestation in Rett syndrome (360G-Wellcome-211415_Z_18_Z)

Seizures in epilepsy and other neurological disorders have a devastating effect on patients and their families. Due to their amenability for genetic manipulation, mouse models of neurological disorders where seizures represent a significant comorbidity represent an exciting opportunity to pinpoint these alterations. One such disorder is the devastating neurological disorder, Rett syndrome (RTT) that affects 1 in 10,000 females. Seizures represent one of the most debilitating symptoms observed in RTT, are frequently atypical absence seizures, lead to a worsening of other symptoms and are often refractory to treatment. Despite their high prevalence, the underlying cellular and circuit mechanisms leading to the manifestation of RTT-associated seizures remain unknown. During this award, I characterise the mechanism of spike-and-wave-type discharges (SpW), a marker of atypical absence seizures, in a mouse model of Rett syndrome. Furthermore, I will evaluate whether reducing the activity of a particular subset of interneurons is sufficient to prevent the generation of SpW activity in these mice. Together, the results from this proposal will uncover the causally important cell types responsible for seizure manifestation in RTT and identify potential new strategies for the control or prevention of these seizures.