Disrupted Vestibular Nuclei Neuron Development in a Chick Model for Congenital Vestibular Disorders

Children with syndromic, congenital vestibular disorders (CVDs) form a sac-like inner ear with missing or truncated semicircular canals and experience delayed motor development with lifelong challenges to maintain posture and balance. How the abnormal inner ear affects downstream central vestibular neural circuitry has not been investigated. We hypothesize that inner ear pathology leads to hyperexcitability and dendritic changes in excitatory vestibular nuclei neurons, as reported for excitatory neurons in other neurodevelopmental disorders. To determine whether neurons in CVDs follow a similar trajectory, we recorded from excitatory vestibular nuclei neurons, the principal cells (PCs) of chick tangential nucleus (TN), in the ARO (anterior-posterior rotated otocyst) chick model for CVDs. In ARO chicks, the otocyst is rotated surgically on one side to produce a sac-like inner ear. Whole-cell patch-clamp recordings on brain slices from 16-day-old (E16) ARO and normal chick embryos showed that spontaneous excitatory currents (sEPSCs) increased significantly in PCs on both sides of ARO chicks compared to PCs from normal chicks. After tetrodotoxin exposure, EPSC frequency decreased about 70% in PCs on both sides of ARO chicks, but only 37% in PCs from normal chicks, suggesting the increased sEPSCs were due to action potential-dependent events. In confocal images, biocytin-injected and recorded PCs had fewer dendritic branches on the rotated side compared to PCs in normal chicks and decreased dendritic volume in PCs on the contralateral side compared to PCs on the rotated side of ARO chicks, indicating failure for the normal dendritic pattern to emerge before birth. Altogether, PCs in ARO chicks were hyperexcitable due to significantly increased action potential-dependent sEPSCs with dendritic developmental defects that collectively represent hallmarks of neurodevelopmental disorders.