A Sensitized IGF1 Treatment Restores Corticospinal Axon-Dependent Functions

Abstract

SUMMARY A major hurdle for functional recovery after both spinal cord injury and cortical stroke is the limited regrowth of the axons in the corticospinal tract (CST) that originate in the motor cortex and innervate the spinal cord. Despite recent advances in engaging the intrinsic mechanisms that control CST regrowth, it remains to be tested whether such methods can promote functional recovery in translatable settings. Here we show that post-lesional AAV-assisted co-expression of two soluble proteins, namely insulin-like growth factor 1 (IGF1) and osteopontin (OPN), in cortical neurons leads to robust CST regrowth, and the recovery of CST-dependent behavioral performance after both T10 lateral spinal hemisection and a unilateral cortical stroke. In these mice, a compound able to increase axon conduction, 4-aminopyridine-3-methanol, promotes further improvement in CST-dependent behavioral tasks. Thus, our results demonstrate a potentially translatable strategy for restoring cortical dependent function after injury in the adult.

IGFBP2 Plays an Essential Role in Cognitive Development during Early Life

“…[4] IGF-1 receptors regulate transmission via mitochondrial mediation in the hippocampus. [6,7] IGF-II enhances memory and prevents forgetting via IGF-II receptors. [6,7] IGF-II enhances memory and prevents forgetting via IGF-II receptors.…”

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

“…Our findings demonstrate the importance of PIP3 in the axon as well the cell body for optimal regeneration. Studies targeting the PTEN/PI3K pathway for CNS axon regeneration examined downstream activation by measuring ribosomal S6 phosphorylation in the cell body (Duan et al, 2015;Liu et al, 2017;Park et al, 2008;Smith et al, 2009), so it is difficult to determine whether these interventions also lead to axonal signalling. The observed increase in axonal PIP3 caused by expression of either p110δ or hyperactive p110α H1047R may be a result of increased axon transport of PI3K-coupled receptors, such has been demonstrated for TrkB in response to BDNF.…”

“…Our study puts forward AAV-mediated delivery of p110δ as a novel means of stimulating regeneration through the PI3K pathway in a potentially translatable fashion. We propose that p110δ should also be considered as an additional intervention with other regenerative strategies that target the PI3K pathway, either through genetic treatment such as osteopotin and IGF-1, (Duan et al, 2015;Liu et al, 2017), expression of activated integrins or pharmacological interventions such as insulin (Agostinone et al, 2018). and obtained funding.…”

Calcium Imaging Reveals Host-Graft Synaptic Network Formation in Spinal Cord Injury

“…In standard artificial cerebrospinal fluid (aCSF) recording solution, grafts displayed spontaneous activity together with responses to stimulation of corticospinal axons that regenerated into the graft occupying the lesion site ( Figure S2D). Addition of the potassium channel blocker 4-aminopyridine (4-AP, 100µM; (Blight et al, 1991;Liu et al, 2017;Strupp et al, 2017)), a drug approved for human use, to the aCSF increased detectable spontaneous activity and responses to corticospinal stimulation (Figure S2E-2G), and was used in most recordings. Episodes of activity in individual neurons were defined as periods of increasing fluorescence (positive first derivative of the change in fluorescence over time, ΔF/F, after noise subtraction) during fluorescence transients that were significantly above noise based on a dynamic threshold incorporating the individual cell's calculated noise model and the decay kinetics of the calcium reporter (Romano et al, 2017).…”