Identification of Intrinsic Axon Growth Modulators for Intact CNS Neurons after Injury

Kathren L. Fink, Francesc López-Giráldez, In-Jung Kim, Stephen M. Strittmatter, William B.J. Cafferty Open Access

•Mechanisms driving functional plasticity of intact CNS circuits are unknown
•Retrograde spinal tracing reveals CST neurons undergoing functional plasticity
•Transcriptional profiling of these neurons reveals pro-axon growth targets
•Molecular modulation of the identified LPA-LPPR1 axis enhances plasticity post-SCI

Functional deficits persist after spinal cord injury (SCI) because axons in the adult mammalian central nervous system (CNS) fail to regenerate. However, modest levels of spontaneous functional recovery are typically observed after trauma and are thought to be mediated by the plasticity of intact circuitry. The mechanisms underlying intact circuit plasticity are not delineated. Here, we characterize the in vivo transcriptome of sprouting intact neurons from Ngr1 null mice after partial SCI. We identify the lysophosphatidic acid signaling modulators LPPR1 and LPAR1 as intrinsic axon growth modulators for intact corticospinal motor neurons after adjacent injury. Furthermore, in vivo LPAR1 inhibition or LPPR1 overexpression enhances sprouting of intact corticospinal tract axons and yields greater functional recovery after unilateral brainstem lesion in wild-type mice. Thus, the transcriptional profile of injury-induced sprouting of intact neurons reveals targets for therapeutic enhancement of axon growth initiation and new synapse formation.

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