Abstract
Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.
Highlights
Studying neurobiological and neuroimmunological processes of neuropsychiatric disorders is limited by a lack of appropriate experimental models
A model of glial dysfunction in SCZ proposed that the activation of microglial cells by inflammation during development could disrupt the proliferation of glial progenitor cells
The impact of inflammatory mechanisms conferred by astrocytes and microglia was studied in the context of SCZ and autism spectrum disorder (ASD)
Summary
Studying neurobiological and neuroimmunological processes of neuropsychiatric disorders is limited by a lack of appropriate experimental models. While neuronal phenotypes in SCZ and ASD diseases have been studied extensively, increasing evidence has linked deregulation of the immune system to neuropsychiatric disorders [20]. Glial cells, such as microglia and astrocytes, represent the innate immune cells of the CNS and closely interact with neurons and their synapses, contributing to proper synaptic connectivity and neuronal activity during development and maturation [21]. Rodent models, post-mortem tissue analysis, and in vivo neuroimaging studies have increased the understanding of aberrant neuron-microglia crosstalk and microglia-mediated neuroinflammation in the context of SCZ or ASD. Mouse models proved that inhibition of C1q or C3 reduced microglia-mediated synapse loss and revealed aberrant synaptic elimination e.g., in a mouse model for Alzheimer’s Disease [43]
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