An antisense oligonucleotide to brain-derived neurotrophic factor delays postural compensation following unilateral labyrinthectomy in guinea pig

Abstract

An antisense oligonucleotide to brain-derived neurotrophic factor (BDNF) was delivered by osmotic mini-pump at a 1 mM concentration via a cannula into the ipsilateral vestibular nucleus complex from 15 to 56h following unilateral labyrinthectomy in guinea pigs. Compared with the control groups, vestibular compensation of roll head tilt was significantly delayed (p < 0.05), while compensation of spontaneous nystagmus and yaw head tilt was unaffected. These results suggest that neurotrophins such as BDNF may be involved in specific aspects of the vestibular compensation process.

Spatiotemporal Dynamics of Brain-Derived Neurotrophic Factor mRNA Induction in the Vestibulo-Olivary Network during Vestibular Compensation

“…Because the BDNF protein product can be transported to axonal terminals (Altar and DiStefano, 1998) and the MVN sends both ipsilateral and contralateral projections to the lateral vestibular nucleus (Ito et al, 1985), the difference between the previous report and our present results might indicate the differential distribution of mRNA and protein product of BDNF in the vestibular nucleus. It was also reported recently that the blockage of BDNF expression by an antisense oligonucleotide in the ipsilateral vestibular nucleus had effects on the recovery of some vestibular symptoms after UL (Bolger et al, 1999). Our present results strongly support this behavioral observation.…”

The effects of intra-vestibular nucleus administration of brain-derived neurotrophic factor (BDNF) on recovery from peripheral vestibular damage in guinea pig

“…One week prior to UL, animals were anesthetised with 0.4 ml/kg i.m fentazin (0.4 mg/ml fentanyl citrate, 58.3 mg/ml xylazine HCl, 3.2 mg/ml azaperone; Parnell, New Zealand) [17] and a cannula was implanted into the right VNC using stereotaxic coordinates (12.5 mm caudal and 1.5 mm lateral to bregma, 10.7 mm ventral to the skull surface) and the procedures we have described in detail previously [13,17]. The cannula was ®xed in place with dental cement and skull screws, and an obturator sealed the cannula when not in use.…”

“…The minipump and associated catheter (see below) had been incubated in 0.9% PBS at 378C overnight so that at the time of the UL it was ready for solution delivery. A right surgical UL was performed as described in detail previously [13,17]. Brie¯y, the right temporal bone was exposed using blunt dissection and, under microscopic control, drilled open to expose the bony labyrinth.…”

“…NTs such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been identi®ed in the VNC [6±9], as have their low af®nity p75 receptors and high af®nity tyrosine kinase (trk) receptors [10±12]. We have previously reported that BDNF expression increases in the lateral VNC with the development of vestibular compensation [8] and that administration of an antisense oligonucleotide to BDNF, but not a mis-sense oligonucleotide, into the ipsilateral VNC results in a signi®cant delay in the compensation of roll head tilt (RHT) following UL in guinea pig [13]. NT-3, but not BDNF or NT-4, knock-out mice have been reported to exhibit a marked delay in postural compensation [14].…”

Une nouvelle zone de neurogenèse fonctionnelle

“…Ceci suggère que la compensation du nystagmus oculaire horizontal spontané reposerait sur d'autres mécanismes de plasticité, qui interviendraient temporellement en amont de la neurogenèse et la gliogenèse [25]. En adéquation avec cette hypothèse, les travaux d'une équipe de chercheurs néo-zélandais ont montré qu'après lésion vestibulaire unilatérale, l'infusion d'oligonucléotides antisens bloquant l'expression du BDNF (facteur favorisant entre autres la neurogenèse) chez la souris conduisait à un retard dans la compensation des déficits posturaux, sans incidence sur le nystagmus oculaire [33]. Dans une autre étude, l'infusion chronique d'antagonistes des récepteurs GABA A dans les NV désafféren-tés a modifié l'expression des symptômes posturaux chez le cochon d'Inde, sans altérer l'expression des symptômes oculomoteurs [34].…”