Regulation of synaptic connectivity in schizophrenia by mutual neuron-microglia interaction

Abstract: The examination of post-mortem brain tissue suggests synaptic loss as a central pathological hallmark of schizophrenia. Synaptic loss has been shown to be related to increased inflammation in the central nervous system. Aberrant activation of microglia, the immune cells of the human brain, may account for neuronal damage in schizophrenia. Induced pluripotent stem cells represent a promising tool for studying neuropsychiatric disease mechanisms. A recent challenge has been the development of protocols to derive microglia as well as neurons from schizophrenia patient-derived stem cells to better understand the mechanistic contribution of neuroinflammation to the disease. To address this, we present a co-culture model of neurons and microglia, both of human origin to show increased susceptibility of neurons to microglia-like cells derived from schizophrenia patients. Analysis of IBA-1 expression, NFκB signaling, transcription of inflammasome-related genes, and caspase-1 activation shows that enhanced, intrinsic inflammasome activation in patient-derived microglia exacerbates neuronal deficits such as synaptic loss in schizophrenia. Anti-inflammatory pretreatment of microglia with minocycline specifically rescued aberrant synapse loss in schizophrenia and reduced microglial activation. These findings open up possibilities for further research in larger cohorts, focused clinical work and longitudinal studies that could facilitate earlier therapeutic intervention.