Astrocyte redox dysregulation causes prefrontal hypoactivity: sulforaphane treats non-ictal pathophysiology in ALDH7A1-mediated epilepsy

摘要: Abstract Mutations in the astrocyte-enriched enzyme aldehyde dehydrogenase 7a1 (ALDH7A1) cause a neonatal epilepsy accompanied by treatment-resistant, inter-ictal neuropsychiatric symptoms. Nevertheless, mechanistic impact of ALDH7A1 dysfunction brain remains elusive. We generated knockout mice and report that constitutive global depletion increases chemoconvulsant sensitivity altered mood-associated behaviors. However, contrary to our expectation, astrocyte-specific only affects Accordingly, mice, we show enhanced redox-sensitive microdomain Ca2+ signaling astrocytes both elevated synaptic inhibitory tone increased dendritic spine density prelimbic pyramidal neurons. Sulforaphane (SFN), an indirect antioxidant dietary supplement, has been explored as possible treatment ameliorate manifestations autism schizophrenia, at least clinical levels, but its mechanism is unclear. Here SFN rescues physiological behavioral changes targeting astrocytic redox imbalance implicating astrocyte creating cortical excitatory-inhibitory mood alteration.