TY - JOUR
T1 - Hyperactive delta isoform of PI3 kinase enables long-distance regeneration of adult rat corticospinal tract
AU - Karova, Kristyna
AU - Polcanova, Zuzana
AU - Knight, Lydia
AU - Suchankova, Stepanka
AU - Nieuwenhuis, Bart
AU - Holota, Radovan
AU - Herynek, Vit
AU - Machova Urdzikova, Lucia
AU - Turecek, Rostislav
AU - Kwok, Jessica C.
AU - van den Herik, Joelle
AU - Verhaagen, Joost
AU - Eva, Richard
AU - Fawcett, James W.
AU - Jendelova, Pavla
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2025/2/5
Y1 - 2025/2/5
N2 - 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.
AB - 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.
KW - axon regeneration
KW - c-Fos
KW - CST
KW - electrophysiology
KW - PI3K
KW - pS6
KW - signaling
KW - skilled paw reaching
KW - spinal cord
KW - spinal cord injury
UR - http://www.scopus.com/inward/record.url?scp=85215387479&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2024.12.040
DO - 10.1016/j.ymthe.2024.12.040
M3 - Article
C2 - 39748509
AN - SCOPUS:85215387479
SN - 1525-0016
VL - 33
SP - 752
EP - 770
JO - Molecular Therapy
JF - Molecular Therapy
IS - 2
ER -