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Background <p>Transcranial direct current stimulation (tDCS) shows promise as a treatment for schizophrenia, but its mechanisms, particularly during critical developmental windows and its impact on neuroimmune cells such as microglia, remain poorly understood.</p> Objective <p>We investigated whether adolescent anodal tDCS could ameliorate behavioral deficits in a maternal immune activation (MIA) mouse model of schizophrenia by rectifying microglial abnormalities.</p> Methods <p>C57BL/6 offspring from Poly I:C- or saline-injected dams received frontal anodal tDCS or sham stimulation during adolescence. Behavioral tests for spontaneous locomotor activity, anxiety, cognition and sensorimotor gating were conducted. Microglial cell count, morphology, and phagocytic activity were assessed in the medial prefrontal cortex (mPFC) and hippocampus via immunofluorescence. Serum cytokines were measured by ELISA, and transcriptomic profiling of brain tissue was performed via RNA-seq.</p> Results <p>MIA offspring exhibited cognitive deficit, accompanied by microglial abnormalities in the mPFC and hippocampus. While adolescent anodal tDCS normalized these phenotypes in MIA mice, it conversely induced cognitive deficits and reduced hippocampal microglial complexity in control mice. Strikingly, tDCS bidirectionally regulated microglial phagocytosis, enhancing it in MIA mice while suppressing it in control mice. RNA-seq of the mPFC revealed that tDCS modulated genes related to neuronal activation (e.g., Fos, JunB) and neural repair (e.g., Sparc), enriching pathways like MAPK signaling and neurotransmitter transport, whereas no significant alterations were observed in the hippocampal transcriptome. Moreover, tDCS elicited a peripheral pro-inflammatory state, elevating serum IL-6 and TNF-α.</p> Conclusion <p>Our findings demonstrated that adolescent anodal tDCS reversed schizophrenia-relevant deficits by promoting microglial normalization in a state- and region-dependent manner, highlighting its potential as an early intervention during critical neurodevelopment.</p> Graphical Abstract <p></p>

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Adolescent anodal tDCS ameliorates behavioral deficits and microglial abnormalities in a maternal immune activation mouse model of schizophrenia

  • 期刊论文

  • 发表日期：

    2026年3月28日

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  • Jiali Shi,
  • Yixin Pan,
  • Yiran Tao,
  • Jie Wang,
  • Jingjing Huang,
  • Weiqing Liu

摘要

Background

Transcranial direct current stimulation (tDCS) shows promise as a treatment for schizophrenia, but its mechanisms, particularly during critical developmental windows and its impact on neuroimmune cells such as microglia, remain poorly understood.

Objective

We investigated whether adolescent anodal tDCS could ameliorate behavioral deficits in a maternal immune activation (MIA) mouse model of schizophrenia by rectifying microglial abnormalities.

Methods

C57BL/6 offspring from Poly I:C- or saline-injected dams received frontal anodal tDCS or sham stimulation during adolescence. Behavioral tests for spontaneous locomotor activity, anxiety, cognition and sensorimotor gating were conducted. Microglial cell count, morphology, and phagocytic activity were assessed in the medial prefrontal cortex (mPFC) and hippocampus via immunofluorescence. Serum cytokines were measured by ELISA, and transcriptomic profiling of brain tissue was performed via RNA-seq.

Results

MIA offspring exhibited cognitive deficit, accompanied by microglial abnormalities in the mPFC and hippocampus. While adolescent anodal tDCS normalized these phenotypes in MIA mice, it conversely induced cognitive deficits and reduced hippocampal microglial complexity in control mice. Strikingly, tDCS bidirectionally regulated microglial phagocytosis, enhancing it in MIA mice while suppressing it in control mice. RNA-seq of the mPFC revealed that tDCS modulated genes related to neuronal activation (e.g., Fos, JunB) and neural repair (e.g., Sparc), enriching pathways like MAPK signaling and neurotransmitter transport, whereas no significant alterations were observed in the hippocampal transcriptome. Moreover, tDCS elicited a peripheral pro-inflammatory state, elevating serum IL-6 and TNF-α.

Conclusion

Our findings demonstrated that adolescent anodal tDCS reversed schizophrenia-relevant deficits by promoting microglial normalization in a state- and region-dependent manner, highlighting its potential as an early intervention during critical neurodevelopment.

Graphical Abstract