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Hyperactive delta isoform of PI3 kinase enables long-distance regeneration of adult rat corticospinal tract
K. Karova, Z. Polcanova, L. Knight, S. Suchankova, B. Nieuwenhuis, R. Holota, V. Herynek, L. Machova Urdzikova, R. Turecek, JC. Kwok, J. van den Herik, J. Verhaagen, R. Eva, JW. Fawcett, P. Jendelova
Language English Country United States
Document type Journal Article
- MeSH
- Axons metabolism physiology MeSH
- Dependovirus genetics MeSH
- Class I Phosphatidylinositol 3-Kinases metabolism genetics MeSH
- Phosphatidylinositol 3-Kinases metabolism MeSH
- Genetic Vectors genetics MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Neurons metabolism MeSH
- Recovery of Function MeSH
- Spinal Cord Injuries * metabolism therapy genetics MeSH
- Pyramidal Tracts * metabolism MeSH
- Nerve Regeneration * MeSH
- Signal Transduction MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Neurons in the CNS lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonizes PI3K signaling by hydrolyzing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study explores whether increased PIP3 generation can promote long-distance regeneration in adults. We used a hyperactive PI3K, PI3Kδ (PIK3CD), to boost PIP3 levels in mature cortical neurons and assessed CST regeneration after SCI. Adult rats received AAV1-PIK3CD and AAV1-eGFP, or AAV1-eGFP alone, in the sensorimotor cortex concurrent with a C4 dorsal SCI. Transduced neurons showed increased pS6 levels, indicating elevated PI3K/Akt/mTOR signaling. CST regeneration, confirmed with retrograde tracing, was evaluated up to 16 weeks post injury. At 12 weeks, ∼100 axons were present at lesion sites, doubling to 200 by 16 weeks, with regeneration indices of 0.1 and 0.2, respectively. Behavioral tests showed significant improvements in paw reaching, grip strength, and ladder-rung walking in PIK3CD-treated rats, corroborated by electrophysiological recordings of cord dorsum potentials and distal flexor muscle electromyography. Thus, PI3Kδ upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post SCI.
Netherlands Institute for Neuroscience Meibergdreef 47 1105 BA Amsterdam the Netherlands
School of Biomedical Sciences University of Leeds Leeds LS2 9JT UK
References provided by Crossref.org
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