Effect of seizures on the severity of myelin vacuolization in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts

ABSTRACT Objective Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a white matter disease characterized by myelin vacuolization and swollen perivascular astrocyte processes. Neuronal activity has been implicated as primary cause of myelin vacuolization and astrocyte swelling. Since acute and excessive increases in neuronal activity occur in MLC during seizures, we investigated whether seizure activity leads to the acute development of myelin vacuoles and swollen astrocyte processes. Methods Glialcam -null mice (an established MLC mouse model) and wild-type mice received repeated i.p. low dose (5 mg / kg) kainic acid (KA) injections until severe seizures developed. Following a 60-minute period of severe seizure activity, mice were terminated and brains were fixed and processed. Brain tissue was analyzed for myelin vacuolization and astrocyte process thickness using H&E and GFAP stains, respectively. Results Repeated low-dose injections of KA resulted in prolonged severe seizure activity in mice of both genotypes. Total amount of seizure activity was comparable between Glialcam -null and wild-type mice. KA-induced severe seizure activity did not significantly increase myelin vacuolization in either Glialcam -null or wild-type mice. The width of perivascular astrocyte processes was also not affected by severe seizure activity. Interpretation We show that (i) repeatedly injecting a low dose of KA provides the opportunity to regulate seizure development and generate severe seizures in both wild-type and seizure-sensitive Glialcam -null mice, and that (ii) the two major pathological features of MLC, myelin vacuolization and swollen astrocyte endfeet, are not acutely aggravated in response to KA-induced severe seizure activity.