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Altered expression of microglial markers of phagocytosis in schizophrenia
Aaron K Jenkins1, David A Lewis2, David W Volk3
1Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States of America.
Background:
Cognitive disturbances in schizophrenia have been linked to a lower density of dendritic spines on pyramidal neurons in the prefrontal cortex (PFC). Complement component C4, which has previously been found at higher levels in schizophrenia, marks synapses for phagocytosis by microglia. Thus, elevated consumption of dendritic spines by microglia mediated through excessive complement activity may play a role in lower spine density in schizophrenia. However, it is unclear if microglia themselves have the molecular capacity for enhanced phagocytosis of spines in schizophrenia.
Methods:
Transcript levels for complement components and microglia-specific phagocytic markers were quantified using quantitative PCR in the PFC of 62 matched pairs of schizophrenia and unaffected comparison subjects and in antipsychotic-exposed monkeys.
Results:
Relative to comparison subjects, schizophrenia subjects had higher mRNA levels for C4 (+154 %); C1q (+69 %), which initiates the classical complement pathway that includes C4; and for microglia-specific markers that enable phagocytic activity including TAM receptor tyrosine kinases Axl (+27 %) and MerTK (+27 %) and lysosome-associated glycoprotein CD68 (+27 %) (all p ≤ .042). Transcript levels for microglial phagocytic markers were correlated with C4 mRNA levels in schizophrenia subjects (all r ≥ 0.31, p ≤ .015). We also found further evidence consistent with microglial activation in schizophrenia, including higher mRNA levels for THIK1 (TWIK-related halothane-inhibited potassium channel: +30 %) and lower mRNA levels for the purinergic receptor P2Y12 (-27 %) (all p ≤ .016). Transcript levels were unchanged in antipsychotic-exposed monkeys.
Conclusions:
These results are consistent with the presence of increased complement activity and an elevated molecular capacity of microglia for phagocytosis in the same schizophrenia subjects.
Insights
Schizophrenia may involve excessive microglial phagocytosis of dendritic spines due to increased complement component C4. This study found elevated complement and microglial phagocytic markers in schizophrenia patients, suggesting a molecular basis for spine loss.
Area of Science:
- Neuroscience
- Immunology
- Psychiatry
Background:
- Cognitive deficits in schizophrenia are linked to reduced dendritic spine density in the prefrontal cortex (PFC).
- Elevated complement component C4 in schizophrenia suggests a role for complement-mediated synaptic pruning.
- The molecular capacity of microglia for enhanced spine phagocytosis in schizophrenia remains unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying microglial phagocytosis of dendritic spines in schizophrenia.
- To quantify transcript levels of complement components and microglial phagocytic markers in the PFC of schizophrenia patients.
Main Methods:
- Quantitative PCR was used to measure mRNA levels of complement components (C4, C1q) and microglial phagocytic markers (Axl, MerTK, CD68, THIK1, P2Y12).
- Samples were obtained from 62 matched pairs of schizophrenia and unaffected comparison subjects, as well as antipsychotic-exposed monkeys.
Main Results:
- Schizophrenia subjects showed significantly higher mRNA levels for C4, C1q, Axl, MerTK, CD68, and THIK1, and lower levels for P2Y12 compared to controls.
- Microglial phagocytic marker transcript levels positively correlated with C4 mRNA levels in schizophrenia subjects.
- No significant changes in transcript levels were observed in antipsychotic-exposed monkeys.
Conclusions:
- The findings support increased complement activity and enhanced microglial phagocytic capacity in schizophrenia.
- These molecular changes in microglia may contribute to the reduced dendritic spine density observed in schizophrenia.
- Antipsychotic treatment did not appear to affect these molecular markers in the monkey model.
