Depolarization of astrocytes in the basolateral amygdala restores WFS1 neuronal activity and rescues impaired risk-avoidance behavior in DISC1TM mice

Summary Many mental illnesses are accompanied by abnormal risk-avoidance behavior, yet we have only a limited understanding of the neuronal regulatory mechanisms involved. We previously established an inducible DISC1-N terminal fragment transgenic mouse ( DISC1-N TM ) model which has exhibited risk-avoidance deficiency. Using this model, we analyzed differentially expressed genes (DEGs) using snRNA-seq and the results indicate impaired neuron-astrocyte interactions. We used optogenetic tools to modulate astrocytes in the basolateral amygdala (BLA) and found that ChR2-expressing astrocytes were able to rescue risk-avoidance impairment in DISC1-N TM mice. Using patch clamp recordings combined with signal-cell qPCR, we found impaired excitability of BLA WFS1 neurons in DISC1-N TM mice and that ChR2-expressing astrocytes can induce action potentials (APs) in WFS1 neurons, which restores WFS1 neuronal activity. WFS1 neurons are necessary for BLA astrocytes to modulate impaired risk-avoidance behavior. These finding provide new insights into mechanisms of astrocyte-neuron interactions and suggest that BLA astrocytes may be a promising target for impaired risk avoidance in mental illness. Highlights ChR2-expressing astrocytes in the BLA rescue impaired risk-avoidance behavior in DISC1-N TM mice. Astrocytes in the BLA modulate different nearby neurons to different degrees. Depolarization of BLA astrocytes restore neuronal activity in WFS1 neurons. Astrocytes in the BLA modulate WFS1 neurons via NMDARs.