Atypical antipsychotics alter microglial functions via astrocyte-derived extracellular vesicles

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Schizophrenia treatment is limited by poor understanding of atypical antipsychotic molecular mechanisms.
• Atypical antipsychotics' effects on non-neuronal cells like astrocytes and microglia are understudied.
• Extracellular vesicles (EVs) mediate cellular communication implicated in schizophrenia etiology, with astrocytes being a major source.

Purpose of the Study:

• To investigate if clozapine and olanzapine affect microglia biology indirectly via astrocyte-secreted EVs.
• To examine the impact of astrocyte-derived EVs (ADEVs) on microglial phagocytosis, motility, and morphology in vitro.

Main Methods:

• Utilized in vitro models with human astrocytes and PBMC-derived microglial-like cells.
• Isolated astrocyte-derived EVs (ADEVs) and treated microglial-like cells.
• Quantified microglial engulfment of synaptosomes to assess phagocytosis and measured microglial motility.

Main Results:

• ADEVs reduced microglial synaptosome phagocytosis in a dose-dependent manner.
• This reduction was reversed by ADEVs from astrocytes treated with norclozapine or olanzapine.
• ADEVs from clozapine-treated astrocytes increased microglial motility, altering surveillance activity.

Conclusions:

• Atypical antipsychotics exert distinct, indirect effects on microglia via ADEVs.
• ADEVs play a critical role in glial cell communication relevant to schizophrenia.
• ADEVs represent potential therapeutic targets for novel antipsychotic drug development.