1. Astrocyte-Specific Overexpression of Insulin-Like Growth Factor-1 Protects Hippocampal Neurons and Reduces Behavioral Deficits following Traumatic Brain Injury in Mice
- Author
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Shaun W. Carlson, Jennifer M. Brelsfoard, Kathryn E. Saatman, Sindhu K. Madathil, A. Joseph D'Ercole, and Ping Ye
- Subjects
Central Nervous System ,Pathology ,Mouse ,lcsh:Medicine ,Hippocampus ,Hippocampal formation ,Behavioral Neuroscience ,0302 clinical medicine ,Cognition ,Learning and Memory ,Brain Injuries, Traumatic ,Neurobiology of Disease and Regeneration ,Psychology ,Gliosis ,Insulin-Like Growth Factor I ,Phosphorylation ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,Glial fibrillary acidic protein ,biology ,Neurodegenerative Diseases ,Animal Models ,Neuroprotection ,Head Injury ,medicine.anatomical_structure ,Mental Health ,Neurology ,Medicine ,medicine.symptom ,Immunohistochemical Analysis ,Astrocyte ,Research Article ,medicine.medical_specialty ,Histology ,Traumatic brain injury ,Cognitive Neuroscience ,Immunology ,Neurophysiology ,Mice, Transgenic ,Brain damage ,Motor Activity ,03 medical and health sciences ,Model Organisms ,Memory ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Humans ,Biology ,030304 developmental biology ,Behavior ,business.industry ,lcsh:R ,medicine.disease ,Animal Cognition ,Disease Models, Animal ,nervous system ,Astrocytes ,Cellular Neuroscience ,biology.protein ,Immunologic Techniques ,lcsh:Q ,Astrocytosis ,Molecular Neuroscience ,business ,Neuroscience ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery - Abstract
Traumatic brain injury (TBI) survivors often suffer from long-lasting cognitive impairment that stems from hippocampal injury. Systemic administration of insulin-like growth factor-1 (IGF-1), a polypeptide growth factor known to play vital roles in neuronal survival, has been shown to attenuate posttraumatic cognitive and motor dysfunction. However, its neuroprotective effects in TBI have not been examined. To this end, moderate or severe contusion brain injury was induced in mice with conditional (postnatal) overexpression of IGF-1 using the controlled cortical impact (CCI) injury model. CCI brain injury produces robust reactive astrocytosis in regions of neuronal damage such as the hippocampus. We exploited this regional astrocytosis by linking expression of hIGF-1 to the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, effectively targeting IGF-1 delivery to vulnerable neurons. Following brain injury, IGF-1Tg mice exhibited a progressive increase in hippocampal IGF-1 levels which was coupled with enhanced hippocampal reactive astrocytosis and significantly greater GFAP levels relative to WT mice. IGF-1 overexpression stimulated Akt phosphorylation and reduced acute (1 and 3d) hippocampal neurodegeneration, culminating in greater neuron survival at 10d after CCI injury. Hippocampal neuroprotection achieved by IGF-1 overexpression was accompanied by improved motor and cognitive function in brain-injured mice. These data provide strong support for the therapeutic efficacy of increased brain levels of IGF-1 in the setting of TBI.
- Published
- 2013