Neuronal Activity Drives Localized Blood-Brain-Barrier Transport of Serum Insulin-like Growth Factor-I into the CNS

Nishijima, Takeshi; Piriz, Joaquín; Duflot, Sylvie; Fernández, Adolfo; Gaitán, Gema; Gómez‐Pinedo, Ulises; Verdugo, José Manuel-García; Leroy, Félix; Soya, Hideaki; Núñez, Ángel; Torres‐Alemán, Ignacio

doi:10.1016/j.neuron.2010.08.007

Cited by 273 publications

(245 citation statements)

References 48 publications

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“…Both groups had similar serum IGF‐1 levels prior to the administration of liver‐targeted viruses (data not shown). Consistent with the concept that circulating IGF‐1 contributes to the maintenance of IGF‐1 levels in the brain (Nishijima et al ., 2010), we found that mice receiving TBG‐Cre‐AAV8 also had significantly lower tissue IGF‐1 levels in the cerebral cortex compared with control mice receiving TBG‐eGFP‐AAV8 (4.8 ± 1.7 and 11.4 ± 2.4 pg mg −1 of tissue, respectively; P = 0.03).…”

Section: Resultsmentioning

confidence: 77%

IGF‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

et al. 2015

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SummaryAging is associated with marked deficiency in circulating IGF‐1, which has been shown to contribute to age‐related cognitive decline. Impairment of moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age‐related cognitive impairment. To establish the link between IGF‐1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF‐1 deficiency (Igf1 f/f‐TBG‐Cre‐AAV8) and accelerated vascular aging. We found that IGF‐1‐deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal‐dependent spatial memory test, mimicking the aging phenotype. IGF‐1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF‐1 deficiency also impaired glutamate‐mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF‐1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment.

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Section: Resultsmentioning

confidence: 77%

IGF‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

et al. 2015

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“…In rats, brain neuronal activity facilitates transport of systemic recombinant human IGF-I across the blood-brain barrier. This process is triggered by a protease which cleaves IGF-I from its dominating binding protein IGFBP-3, allowing free IGF-I to enter the endothelial barrier, using specific transport proteins (18). Furthermore, systemic administration of IGF-I modulates brain vessel growth and cognitive function in mice, suggesting a link between circulatory derived IGF-I and IGF-I within the brain (19,20).…”

Section: Discussionmentioning

confidence: 99%

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

et al. 2013

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“…Another major activator of these signaling pathways is insulinlike growth factor-1 (IGF1), which is primarily expressed in the liver and acts in an endocrine fashion throughout the body, crossing the BBB in a neuronal activity-dependent manner (14); IGF1 is also produced in the brain, especially during early stages of development (15,16). A previous study showed that administering the tripeptide fragment Glutamate-Proline-Glycine (GPE) or (1-3)IGF1, the first 3 (of 70) amino acids of IGF1, to Mecp2 KO mice was effective in correcting several symptoms and restoring key synaptic molecules (5).…”

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confidence: 99%

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

Castro

Garcia

Kwok

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

178

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Rett Syndrome is a neurodevelopmental disorder that arises from mutations in the X-linked gene methyl-CpG binding protein 2 (MeCP2). MeCP2 has a large number of targets and a wide range of functions, suggesting the hypothesis that functional signaling mechanisms upstream of synaptic and circuit maturation may contribute to our understanding of the disorder and provide insight into potential treatment. Here, we show that insulin-like growth factor-1 (IGF1) levels are reduced in young male Mecp2-null (Mecp2 −/y ) mice, and systemic treatment with recombinant human IGF1 (rhIGF1) improves lifespan, locomotor activity, heart rate, respiration patterns, and social and anxiety behavior. Furthermore, Mecp2-null mice treated with rhIGF1 show increased synaptic and activated signaling pathway proteins, enhanced cortical excitatory synaptic transmission, and restored dendritic spine densities. IGF1 levels are also reduced in older, fully symptomatic heterozygous (Mecp2 −/+ ) female mice, and short-term treatment with rhIGF1 in these animals improves respiratory patterns, reduces anxiety levels, and increases exploratory behavior. In addition, rhIGF1 treatment normalizes abnormally prolonged plasticity in visual cortex circuits of adult Mecp2 −/+ female mice. Our results provide characterization of the phenotypic development of Rett Syndrome in a mouse model at the molecular, circuit, and organismal levels and demonstrate a mechanism-based therapeutic role for rhIGF1 in treating Rett Syndrome. molecular therapeutic | respiration | synaptic function | male mice | female mice R ett Syndrome (RTT) is a devastating, rare neurodevelopmental disorder that primarily afflicts girls. Over 90% of individuals with RTT have sporadic mutations in the X-linked gene coding for methyl-CpG binding protein 2 (MeCP2). Affected girls are initially asymptomatic, but later develop a wide range of symptoms. Mouse models of RTT with deletion of Mecp2 recapitulate many of the key physiological, autonomic, motor, and cognitive aspects of the disorder (1, 2).MeCP2 binds widely across the genome and has complex roles that encompass activating or inhibiting gene transcription, repressing methylation, regulating chromatin remodeling, and altering noncoding RNAs (3). This wide range of functions has led to the proposal that a focus on functional signaling pathways is needed to drive an understanding of RTT and its possible therapeutics (1, 2, 4). Several lines of evidence indicate an arrested brain maturation phenotype in RTT, suggesting that loss of functional MeCP2 leads to immature synapses and circuits in the brain (5). Importantly, mouse models have suggested reversibility of specific symptoms once MeCP2 function is restored (6, 7). One well-documented target of MeCP2 is brain-derived neurotrophic factor (BDNF), which is known to be critical for neuronal and synaptic maturation and is down-regulated in Mecp2 mutant mice and RTT patients (8, 9). BDNF exerts influence on neurons and synapses mainly via the phosphoinositide 3-kinase (PI3K)/Akt pathway ...

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Neuronal Activity Drives Localized Blood-Brain-Barrier Transport of Serum Insulin-like Growth Factor-I into the CNS

Cited by 273 publications

References 48 publications

IGF‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

IGF‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

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