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) from astrocytes are implicated in schizophrenia and may mediate drug effects.

Purpose of the Study:

• To investigate how clozapine and olanzapine affect microglia biology indirectly via astrocyte-derived EVs (ADEVs).
• To determine the impact of ADEVs on microglial phagocytosis, motility, and morphology relevant to schizophrenia.

Main Methods:

• Primary human astrocytes and PBMC-derived microglial-like cells were used in in vitro models.
• Astrocyte-derived EVs (ADEVs) were isolated and applied to microglial cells.
• Microglial phagocytosis of synaptosomes and motility were quantified using image-based methods.

Main Results:

• ADEVs reduced microglial phagocytosis of synaptosomes 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.
• ADEVs represent potential therapeutic targets for novel antipsychotic drug development.