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

Abstract

Mutations in the astrocyte-enriched enzyme aldehyde dehydrogenase 7a1 (ALDH7A1) cause a neonatal epilepsy accompanied by treatment-resistant, inter-ictal neuropsychiatric symptoms. Nevertheless, the mechanistic impact of ALDH7A1 dysfunction in the brain remains elusive. We generated ALDH7A1 knockout mice and report that constitutive global ALDH7A1 depletion increases chemoconvulsant sensitivity and altered mood-associated behaviors. However, contrary to our expectation, astrocyte-specific ALDH7A1 depletion only affects mood-associated behaviors. Accordingly, in astrocyte-specific ALDH7A1 knockout mice, we show enhanced redox-sensitive microdomain Ca ²⁺ signaling in astrocytes and both elevated synaptic inhibitory tone and increased dendritic spine density in prelimbic pyramidal neurons. Sulforaphane (SFN), an indirect antioxidant and dietary supplement, has been explored as a possible treatment to ameliorate neuropsychiatric manifestations in autism and schizophrenia, at least at the clinical levels, but its mechanism in the brain is unclear. Here we show that SFN rescues both the physiological and behavioral changes by targeting astrocytic redox imbalance in ALDH7A1 knockout mice, implicating astrocyte redox changes in creating cortical excitatory-inhibitory imbalance and mood alteration.