A Role for Insulin‐like Growth Factor 1 in the Generation of Epileptic Spasms in a murine model
- 10 May 2022
- journal article
- research article
- Published by Wiley in Annals of Neurology
- Vol. 92 (1), 45-60
- https://doi.org/10.1002/ana.26383
Abstract
Objective Infantile spasms are associated with a wide variety of clinical conditions, including perinatal brain injuries. We have created a model in which prolonged infusion of tetrodotoxin (TTX) into the neocortex, beginning in infancy, produces a localized lesion and reproduces the behavioral spasms, electroencephalogram (EEG) abnormalities, and drug responsiveness seen clinically. Here, we undertook experiments to explore the possibility that the growth factor IGF-1 plays a role in generating epileptic spasms. Methods We combined long-term video EEG recordings with quantitative immunohistochemical and biochemical analyses to unravel IGF-1's role in spasm generation. Immunohistochemistry was undertaken in surgically resected tissue from infantile spasms patients. We used viral injections in neonatal conditional IGF-1R knock-out mice to show that an IGF-1-derived tripeptide (1-3)IGF-1, acts through the IGF-1 receptor to abolish spasms. Results Immunohistochemical methods revealed widespread loss of IGF-1 from cortical neurons, but an increase in IGF-1 in the reactive astrocytes in the TTX-induced lesion. Very similar changes were observed in the neocortex from patients with spasms. In animals, we observed reduced signaling through the IGF-1 growth pathways in areas remote from the lesion. To show the reduction in IGF-1 expression plays a role in spasm generation, epileptic rats were treated with (1-3)IGF-1. We provide 3 lines of evidence that (1-3)IGF-1 activates the IGF-1 signaling pathway by acting through the receptor for IGF-1. Treatment with (1-3)IGF-1 abolished spasms and hypsarrhythmia-like activity in the majority of animals. Interpretation Results implicate IGF-1 in the pathogenesis of infantile spasms and IGF-1 analogues as potential novel therapies for this neurodevelopmental disorder. ANN NEUROL 2022Funding Information
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (1U54 HD083092)
- National Institute of Neurological Disorders and Stroke (R61/R33 NS112553, RO1 NS018309, RO1 NS105913)
This publication has 51 references indexed in Scilit:
- De novo mutations in epileptic encephalopathiesNature, 2013
- Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delayMolecular Autism, 2013
- Molecular Basis of Signaling Specificity of Insulin and IGF Receptors: Neglected Corners and Recent AdvancesFrontiers in Endocrinology, 2012
- Activity-Dependent IGF-1 Exocytosis Is Controlled by the Ca2+-Sensor Synaptotagmin-10Cell, 2011
- A model of symptomatic infantile spasms syndromeNeurobiology of Disease, 2010
- Suppression of the Intrinsic Apoptosis Pathway by Synaptic ActivityJournal of Neuroscience, 2010
- Temporal and Regional Changes in IGF-1/IGF-1R Signaling in the Mouse Brain after Traumatic Brain InjuryJournal of Neurotrauma, 2010
- Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastomaNeuro-Oncology, 2009
- Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant miceProceedings of the National Academy of Sciences of the United States of America, 2009
- Identification of Gly-Pro-Glu (GPE), the aminoterminal tripeptide of insulin-like growth factor 1 which is truncated in brain, as a novel neuroactive peptideBiochemical and Biophysical Research Communications, 1989