Inhibition of aberrant astrocyte activity restores auditory sensorimotor function in zebrafish spen mutants

Sensorimotor deficits can profoundly affect the life quality of patients with neurological disorders, yet our understanding of central dysfunction at the cellular or circuit level is limited. Using a forward genetic approach to generate loss of auditory function in zebrafish larvae, we identified a recessive mutation in split ends ( spen ), which encodes a transcription factor implicated in neurodevelopmental disorders in humans. We found that auditory sensorimotor deficits in spen mutants are associated with chronically elevated calcium levels in hindbrain radial astrocytes. Astrocytes have been previously implicated in the integration of neuronal inputs that alter arousal states and sensorimotor behavior. Inhibition of noradrenergic receptors, which are expressed in astrocytes, lowered calcium levels in mutant radial astrocytes and, notably, restored behavioral responses to sound in spen mutants. Our study highlights a role for noradrenergic signaling in spen -related disease and points to potential therapeutic approaches for pediatric patients.