Abstract P835: Long Noncoding RNA FosDT is Developmentally Dispensable but Critical for Shaping the Therapeutic Post-Stroke Functional Outcome

Abstract

Stroke induces the expression of several long noncoding RNAs (lncRNAs) in the brain. However, their functional significance in post-stroke outcome is poorly understood. We recently observed that a brain-specific lncRNA called Fos downstream transcript (FosDT) is induced rapidly in rodent brain following focal ischemia. We here show that FosDT expression is developmentally regulated with adults specifically display higher expression in the cerebral cortex than neonates. To understand its significance in ischemic brain damage, we developed FosDT knockout rats using CRISPR-Cas9 genome editing. We found that FosDT knockout rats did not show any anomalies in growth and development, fertility, brain cytoarchitecture and cerebral vasculature. However, when subjected to transient focal ischemia, FosDT knockout rats of both sexes showed enhanced sensorimotor recovery and reduced brain damage. To further understand the mechanistic implications of FosDT in the ischemic brain, we conducted RNA-seq analysis. The result showed that improved post-stroke functional outcome in FosDT knockout rats is partially associated with curtailed post-ischemic induction of inflammatory genes. When rats subjected to transient focal ischemia were treated with FosDT siRNA, there was significant neuroprotection and better functional outcome irrespective of sex and age. FosDT siRNA was efficacious when administered peripherally and also in a delayed manner. Thus, preventing FosDT activation is beneficial for the post-stroke outcome.