Astrocyte-Specific Overexpression of Insulin-Like Growth Factor-1 Protects Hippocampal Neurons and Reduces Behavioral Deficits following Traumatic Brain Injury in Mice

Autor: Shaun W. Carlson, Jennifer M. Brelsfoard, Kathryn E. Saatman, Sindhu K. Madathil, A. Joseph D'Ercole, Ping Ye
Rok vydání: 2013
Předmět:
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
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 6, p e67204 (2013)
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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