Targetting microglia activation in schizophrenia by minocycline treatment

The importance of the brain's phagocyte – the microglia – came recently into focus as a novel therapeutic target in psychiatric disorders. Dysregulations of microglia have been reported in post mortem tissue and also in vivo by increased radio ligand binding to the (phagocyte-specific) TSPO receptor in brains of schizophrenic patients. The tetracycline minocycline that partially acts on microglia has been shown to improve mainly negative symptoms in a few clinical studies. We here use an animal model of maternal immune activation to test its validity for clinical translation and investigate the pathways that are targeted by minocycline specific in microglia. Pregnant dams were injected intraperitoneally with the viral mimic PolyI:C or saline at gestational day 15 and the offspring was tested for behavioral deficits at postnatal day 60. Indeed, the offspring showed behavioral correlates of schizophrenia like decreased pre-pulse inhibition, sociability and cognitive performance along with an increased binding potential to the TSPO shown by autoradiography using [¹⁸F]GE-180 on hippocampal slices. This was accompanied by a profoundly altered transcriptome signature in hippocampal microglia and decreased phagocytic activity. Thereafter, mice were treated for five weeks with minocycline (3 mg/kg/day). This treatment normalized the behavioral deficits, TSPO binding and phagocytic activity and restored the transcriptome signature towards control levels. Our findings indicate that minocycline is a potent drug to affect specific microglial functions and thereby attenuate symptoms of schizophrenia in an animal model.