Cell Type-Specific Gene Expression and Editing Responses to Chronic Fluoxetine Treatment in the In Vivo Mouse Brain and Their Relevance for Stress-Induced Anhedonia

Recently developed methods for fluorescence-activated cell sorting (FACS) of freshly-isolated brain cells from transgenic mice combining fluorescent signals with cell type-specific markers allow cell-type separation. Based upon previous observations in primary cultures of mouse astrocytes we treated transgenic mice tagged with a neuron-specific or an astrocyte-specific marker with fluoxetine, either acute (10 mg/kg for 2 h) or chronic (10 mg/kg daily for 2 weeks). Acute treatment upregulated cfos and fosB mRNA expression in astrocytes and neurons. Chronic effects on astrocytes replicated those demonstrated in cultures, i.e., upregulation of mRNA and/or protein expression of 5-HT2B receptors (5-HT2BR), and GluK2 receptors, and of cPLA(2a) and ADAR2, together with increased GluK2 and 5-HT2BR editing. Neurons showed increased GluK4 and 5-HT2C receptor expression. To further correlate these findings with major depression we compared the changes in gene expression with those in a mouse model of anhedonia. Three out of 4 genes up-regulated in astrocytes by fluoxetine were down-regulated, whereas the neuronally upregulated 5-HT2C receptor gene showed no change. References are made to recent review papers discussing potential relations between observed fluoxetine effects and clinical effects of SSRIs, emphasizing that all 5 clinically used SSRIs have identical and virtually equipotent effects on cultured astrocytes.