Epilepsy is a brain disorder that affects nearly ten million children globally and can impact their overall well-being and long-term health. This condition is characterized by an excess of electrical signals in the brain and the presence of recurrent unprovoked seizures, which may appear during the first days of life and persist through childhood and adolescence. The causes of epilepsy are linked to genetic variants within genes involved in brain excitability, such as ion channels, which can influence how neurons form connections and, in turn, how neurons communicate. The potassium ion channel, KCNB1, controls potassium flux across membranes and represses neural hyperexcitability. In children, KCNB1 gene variants are linked to early-onset epilepsy and correlate with signs of brain inflammation, neuronal atrophy, and behavioral deficits, which highlights the influence of KCNB1 in neurodevelopment. Remarkably, mice with Kcnb1 variants exhibit not only similar brain alterations to those observed in children, such as the presence of repeated seizures during the juvenile period, but also display aberrant expression of proteins involved in epigenetic regulation, such as histone deacetylases (HDACs).

This research aims to study epigenetic mechanisms underlying the early onset of seizures using a mouse model of Kcnb1 dysfunction. To this end, we will focus on Histone Deacetylase 1 (HDAC1), an epigenetic enzyme that fine-tunes gene expression and plays an important role in neurodevelopment. For this, we will first explore the contribution of HDAC1 in brain connectivity, neural activity, and neuroinflammatory processes by manipulating its expression in newborn mice with Kcnb1 dysfunction. We will then examine the impact of early life HDAC1 manipulation on social and emotional behaviors as well as on the presence of seizure episodes during the juvenile period.

Collectively, our research looks at a crucial time in mouse development, from newborn to juvenile, when the brain is still growing and the risk for epilepsy is high. Our findings, therefore, will set the basis for epigenetic therapeutics for children who develop epilepsy early in life, which could potentially improve their long-term health and overall well-being.