Enhancing corticospinal tract neurite outgrowth using histone deacetylase inhibitors

The human corticospinal tract (CST) is responsible for coordinated voluntary movement and it contains descending afferent inputs involved in autonomic control and gating of spinal reflexes. After spinal cord injury (SCI), damage to the CST causes degeneration of axons and can result in major motor impairments. The CST is especially lacking in its capacity to regenerate after injury. In the current study, we harvested the cortices of postnatal day 8 Thy1YFP16JRS mice, which express YFP in layer five projection neurons, which also express CST transcription factors Ctip2 and Otx1 in vitro. We applied Histone deacetylase (HDAC) inhibitors (Trichostain A [TSA] and Tubastatin A) to the mixed neuron culture and assessed survival and neurite outgrowth of YFP positive CST neurons. TSA treatment increased the number of primary neurites per neuron and the number of branch points exhibited by YFP positive CST neurons. Application of either TSA or Tubastatin A, promoted YFP positive CST neurite outgrowth in baseline media as well as in the presence of the neurotrophin 3 (NT3) and cilliary neurotrophic factor (CNTF), compared to the appropriate controls. Taken together, the application of HDAC inhibitors to postnatal corticospinal neurons can promote neurite outgrowth, branching and an increase in the number of primary neurites when grown in baseline media.Medicine, Faculty ofGraduat