Loss of Neuronal Imp Contributes to Seizure Behavior through Syndecan Function

Seizures affect a large proportion of the global population and occur due to abnormal neuronal activity in the brain. Unfortunately, widespread genetic and phenotypic heterogeneity contributes to insufficient treatment options. It is critical to identify the genetic underpinnings of how seizures occur to better understand seizure disorders and improve therapeutic development. We used the <i>Drosophila melanogaster</i> model to identify that IGF-II mRNA-binding protein (Imp) is linked to the onset of this phenotype. Specific reduction of Imp in neurons causes seizures after mechanical stimulation. Importantly, gross motor behavior is unaffected, showing Imp loss does not affect general neuronal activity. Developmental loss of Imp is sufficient to cause seizures in adults; thus, Imp-modulated neuron development affects mature neuronal function. Since Imp is an RNA-binding protein, we sought to identify the mRNA target that Imp regulates in neurons to ensure proper neuronal activity after mechanical stress. We find that the Imp protein binds <i>Syndecan</i> (<i>Sdc</i>) mRNA, and the reduction of Sdc also causes mechanically induced seizures. Expression of Sdc in <i>Imp</i>-deficient neurons rescues seizure defects, showing that Sdc is sufficient to restore normal behavior after mechanical stress. We suggest that the Imp protein binds <i>Sdc</i> mRNA in neurons, and this functional interaction is important for normal neuronal biology and animal behavior in a mechanically induced seizure model. Since Imp and Sdc are conserved, our work highlights a neuronal-specific pathway that might contribute to seizure disorder when mutated in humans.