Insulin‐like Growth Factor I Regulates Astrocyte Function

Abstract

Age‐related alterations in the communication between neurons, glia, and the vasculature contribute to the onset of vascular cognitive impairment. Growth signals, such as insulin‐like growth factor I (IGF‐1), have been shown to positively regulate neurovascular coupling. Unfortunately, IGF‐1 levels markedly decrease with age, increasing the likelihood of disrupted neurovascular coupling and subsequent cognitive impairment. Several studies have examined the mechanisms by which IGF‐1 regulates the neuronal excitability and vascular function; however, there are few studies that examine how IGF‐1 influences the glial component of the neuro‐glio‐vascular unit. Astrocytes serve as a key regulator of the communication between neurons and the vasculature. Moreover, astrocytes provide critical energetic support, buffer neurotoxic signals, and release a variety of trophic factors. If IGF‐1 is important for the function of astrocytes, then the age‐related loss of IGF‐1 could have damaging consequences for neurovascular function. In this series of experiments, we have begun to address how IGF‐1 influences the ability of astrocytes to support neurovascular coupling.To target IGF‐1 signaling, astrocytes from IGFRf/f mice were grown in culture and treated with AAV2/8‐CMV‐Cre or control AAV2/8‐CMV‐GFP. Decrease in IGFR expression was verified using qRT‐PCR and Western blot analysis. The expression of trophic factors and glutamate/ATP/NO signaling pathways was then assessed in the IGFR‐deficient astrocytes. Expression of several growth factors, including BDNF and VEGF, was significantly decreased in astrocytes lacking IGFR, suggesting that the trophic support supplied by astrocytes may be reduced when IGF‐1 signaling is impaired. There was also a reduction in the expression of several metabotropic glutamate receptors and purinergic receptors when IGFR was knocked‐down, suggesting that the loss of IGF‐1 signaling may be detrimental for astrocytic activation. If astrocytes are unable to respond to appropriately respond to signals from neurons, it is likely that release of factors that regulate vascular tone would also be impaired in these astrocytes. Thus, we next measured the ability of astrocytes to release vasoregulators with and without stimulation. Interestingly, IGFR knockout resulted in decreased release of PGE2 under control, glutamate‐stimulated, or IGF‐1 stimulated conditions. This highlights a critical role for IGF‐1 in the regulation of the vascular tone.Together, our study shows that IGF‐1 signaling influences the ability of astrocytes to provide trophic support, respond to excitatory stimulation, and release vasoregulators. In addition to our in vitro studies, we are currently examining the effects of astrocytic IGFR knockdown in vivo. IGFRf/f mice were crossed with GFAP‐Cre/Ert2. Following administration of tamoxifen, IGFR expression is decreased in the GFAP‐positive astrocytes. Spatial learning and memory as well as neurovascular coupling will be assessed to determine whether the loss of IGFR signaling influences hippocampal and/or cortical function.