Loss of insulin-like growth factor-1 signaling in astrocytes disrupts glutamate handling

Insulin-like Growth Factor-1 (IGF-1) has been studied extensively for its ability to promote neuronal growth and excitability. Declining levels of IGF-1 have been correlated with impaired learning and memory as well as an increased risk of neurodegenerative diseases. While neuronal regulation by IGF-1 is well understood, the role of IGF-1 in influencing astrocyte function requires further exploration. Astrocytes regulate many aspects of the brain microenvironment, including controlling glutamate-glutamine cycling, which ultimately supports neuronal metabolism, neurotransmission, and protection from over stimulation. In this study, we examined whether IGF-1 acts through its cognate receptor, IGFR, to alter astrocytic glutamate handling. We utilized both small molecule IGFR inhibitors and Cre-driven genetic approaches to reduce IGFR in vivo and in cultured rodent astrocytes. When IGFR was knocked out of primary astrocytes derived from igfr^f/f mice using AAV5-CMV-Cre, significant reductions in glutamate uptake were observed. Similarly, inhibition of IGFR with picropodophyllotoxin for 2 h, as well as 24 h, reduced glutamate uptake in vitro. Mechanistically, short-term inhibition of IGFR resulted in a significant decrease in glutamate transporter availability on the cell surface, as assessed by biotinylation. Long-term inhibition of IGFR led to significant reductions in mRNA expression of glutamate transport machinery, as assessed with qPCR. Reduced glutamate transporter mRNA was also observed in the brains of astrocyte-specific IGFR-deficient mice, three to four months after knock-out was induced with tamoxifen. Interestingly, long-term IGF-1 inhibition also resulted in an increase in adenosine triphosphate-stimulated glutamate release, though no change in adenosine triphosphate-stimulated calcium flux was observed nor were any changes in purinergic receptor protein expression. Together, these data suggest that reduced IGF-1 signaling will favor an accumulation of extrasynaptic glutamate, which may contribute to neurodegeneration in disease states where IGF-1 levels are low. Cover Image for this issue: doi: 10.1111/jnc.14534.