NT-3

Background: Spinal cord injury (SCI) is a serious medical problem, leading to lifelong disability and increasing the health burden worldwide. Traditional treatments have limited effects on neuronal function recovery. Previous studies showed that neurotrophin-3 (NT-3) promoted oligodendrocyte survival and improved neuronal functional recovery after SCI. However, the mechanism by which NT-3 promotes oligodendrocyte survival after SCI remains unclear, which limits its application. Materials and methods: A total of 75 female Sprague-Dawley rats were randomly divided into three groups: the NS group, NT-3 group, and NT-3 + rapamycin group. After successful modeling, the spinal cord specimens were taken at the corresponding time points. Western blot was used to detect autophagy-related proteins and Olig1 protein expression and combined with pathology, immunohistochemistry, flow cytometry, and other methods to detect the proliferation of oligodendrocytes after NT-3 application. Results: NT-3 was found to significantly promote the recovery of motor function by Basso-Beattie-Bresnahan scores analysis in the rat SCI model. Furthermore, intraspinal administration of NT-3 could downregulate the expression of Beclin-1 in oligodendrocytes, indicating that NT-3 could inhibit excessive autophagy of oligodendrocytes after SCI. The effects of NT-3 on oligodendrocyte survival could be blocked by an autophagy activator rapamycin. Conclusions: This study found that NT-3 could promote the recovery of motor function after SCI in rats. The underlying reason may be that NT-3 inhibits the expression of autophagy proteins in oligodendrocytes and promotes oligodendrocyte proliferation. This study provided evidence for the future clinical application of NT-3 in SCI patients.

With the development of neural prostheses, neural plasticity including synaptic remodeling under electrical stimulation is drawing more and more attention. Indeed, intracochlear electrical stimulation used to restore hearing in deaf can induce the loss of residual hearing and synapses of the inner hair cells (IHCs). However, the mechanism under this process is largely unknown. Considering that the guinea pig is always a suitable and convenient choice for the animal model of cochlea implant (CI), in the present study, normal-hearing guinea pigs were implanted with CIs. Four-hour electrical stimulation with the intensity of 6 dB above electrically evoked compound action potential (ECAP) threshold (which can decrease the quantity of IHC synapses and the excitability of the auditory nerve) resulted in the upregulation of Bdnf (p < 0.0001) and downregulation of Nt-3 (p < 0.05). Intracochlear perfusion of exogenous NT-3 or TrkC/Fc (which blocks NT-3) can, respectively, resist or aggravate the synaptic loss induced by electrical stimulation. In contrast, local delivery of exogenous BDNF or TrkB/Fc (which blocks BDNF) to the cochlea, respectively, exacerbated or protected against the synaptic loss caused by electrical stimulation. Notably, the synaptic changes were only observed in the basal and middle halves of the cochlea. All the findings above suggested that NT-3 and BDNF may play opposite roles in the remodeling of IHC synapses induced by intracochlear electrical stimulation, i.e. NT-3 and BDNF promoted the regeneration and degeneration of IHC synapses, respectively.

Trk-A is a receptor tyrosine kinase (RTK) that plays an essential role in the development and functioning of the nervous system. Trk-A is expressed in neurons and signals in response to two ligands, NGF and neurotrophin-3 (NT-3), with very different functional consequences. Thus, NGF and NT-3 are "biased" ligands for Trk-A. Because it has been hypothesized that biased RTK ligands induce differential stabilization of RTK dimers, here, we seek to test this hypothesis for NGF and NT-3. In particular, we use Förster resonance energy transfer (FRET) and fluorescence intensity fluctuation spectroscopy to assess the strength of Trk-A interactions and Trk-A oligomer size in the presence of the two ligands. Although the difference in Trk-A behavior in response to the two ligands has been previously attributed to differences in their binding to Trk-A in the endosomes at low pH, here, we further show differences in the stabilities of the NGF- and NT-3-bound Trk-A dimers in the plasma membrane and at neutral pH. We discuss the biological significance of these new findings and their implications for the design of Trk-A ligands with novel functionalities.