Identification of intrinsic growth modulators for intact CNS neurons after injury

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 circuits. 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. Overall design: GFP labeled Corticospinal motor neurons (CSMNs) were harvetsed via laser capture microdissection to assess gene expression between populations that were quiescent and those that initated a functional axon growth response.

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Fink KL, López-Giráldez F, Kim IJ, Strittmatter SM, Cafferty WBJ