When sense environmental changes, astrocytes become “reactive astrocytes” and encode them into unique Ca²⁺ signals that affect greatly contribute to physiological and pathophysiological brain functions. Here, we show that reactive astrocyte-mediated Ca²⁺signals are decoded into synapse remodeling in the primary somatosensory cortex (S1) and the hippocampus. After peripheral nerve injury, we found that S1 cortical astrocytes become reactive and show frequent Ca²⁺ signals. The Ca²⁺ responses were initiated by upregulation of mGluR5, followed by release of multiple synaptogenic molecules such as TSP-1 and Glypican4, and excess uncontrolled synapse formation. Then, S1 astrocytes caused misconnection of tactile- and pain-networks, thereby leading to sustained mechanical allodynia. In the epileptogenesis model, hippocampal astrocytes also become reactive, and encode them into interesting Ca²⁺ signals, which were also triggered by mGluR5. The Ca²⁺ signals in the reactive astrocytes are decoded into synaptogenesis and network remodeling in the hippocampus, thereby leading to epileptogenesis. Taken together, the unique Ca²⁺signals seen in reactive astrocytes could be decoded into excess synaptogenesis, which are greatly involved in brain diseases.