Neuronal hyper-excitability through an excitatory molecule derived from reactive astrocytes.

Abstract

In reaction to brain injury, infection, or disease, astrocytes alter their molecular profile and morphology dramatically, developing into reactive astrocytes. Reactive astrocytes show dysregulation of the Ca²⁺ dynamics, a proxy for the astrocytic activity, which could result in deleterious effects on synapses and neurons in disease. Among molecules that underlie the Ca²⁺ dysregulation, P2Y1 receptor (P2Y1R) could be a key molecule for several neurological diseases such as epilepsy, stroke, and Alzheimer’s disease, which is activated by extracellular ATP or ADP. However, the functional significance of the upregulation is largely unclear. Also, whether common downstream effector(s) acting neurons has not been clarified. To tackle these problems, we have used transgenic mice in which astrocytes specifically overexpress P2Y1R (AstroP2Y1OE). We found that AstroP2Y1OE induces neuronal hyper-excitability. To elucidate its cellular mechanism, we performed Ca²⁺ imaging of neurons and astrocytes, RNA-seq, slice electrophysiology, and immunohistochemistry. Then, we found that AstroP2Y1OE enhances neuronal excitation through the upregulation of IGFBP2, a secretory excitatory molecule, in astrocytes. Furthermore, P2Y1R and IGFBP2 were commonly co-upregulated in reactive astrocytes in seizure and stroke models. Overall, our data indicate a novel mechanism underlying neuronal hyper-excitability mediated by IGFBP2 derived from astrocytes upregulating P2Y1R in neurological diseases.