A Sensitized IGF1 Treatment Restores Corticospinal Axon-Dependent Functions

Yuanyuan Liu; Xuhua Wang; Wenlei Li; Qian Zhang; Yi Li; Zicong Zhang; Junjie Zhu; Bo Chen; Philip R Williams; Yiming Zhang; Bin Yu; Xiaosong Gu; Zhigang He

doi:10.1016/j.neuron.2017.07.037

A Sensitized IGF1 Treatment Restores Corticospinal Axon-Dependent Functions

Neuron. 2017 Aug 16;95(4):817-833.e4. doi: 10.1016/j.neuron.2017.07.037.

Authors

Yuanyuan Liu¹, Xuhua Wang¹, Wenlei Li², Qian Zhang³, Yi Li¹, Zicong Zhang¹, Junjie Zhu¹, Bo Chen¹, Philip R Williams¹, Yiming Zhang¹, Bin Yu⁴, Xiaosong Gu⁴, Zhigang He⁵

Affiliations

¹ F.M. Kirby Neurobiology Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
² F.M. Kirby Neurobiology Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210004, China.
³ F.M. Kirby Neurobiology Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an 710032, China.
⁴ Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
⁵ F.M. Kirby Neurobiology Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: zhigang.he@childrens.harvard.edu.

Abstract

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.

Keywords: 4-aminopyridine; IGF1; axon regeneration; axon sprouting; ischemic stroke; osteopontin; spinal cord injury.

MeSH terms

Age Factors
Aminopyridines / pharmacology
Animals
Axotomy
Disease Models, Animal
Functional Laterality
Hindlimb / physiopathology
Insulin-Like Growth Factor I / pharmacology
Insulin-Like Growth Factor I / therapeutic use*
Mice
Movement Disorders / drug therapy
Movement Disorders / etiology
Neurons / drug effects*
Osteopontin / pharmacology
Osteopontin / therapeutic use*
Psychomotor Performance / drug effects
Psychomotor Performance / physiology
Pyramidal Tracts / pathology*
Recovery of Function / drug effects*
Recovery of Function / physiology
Reflex / drug effects
Reflex / genetics
Serotonin / metabolism
Spinal Cord Injuries / drug therapy*
Stroke / drug therapy
Time Factors

Substances

Aminopyridines
Osteopontin
Serotonin
Insulin-Like Growth Factor I
4-aminopyridine methiodide

Abstract

MeSH terms

Substances

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