Perivascular macrophage depletion impairs glymphatic clearance and amplifies cortical hyperexcitability: Preclinical insights with clinical validation.

Perivascular macrophages (PVMs) are increasingly recognized as key players in maintaining brain homeostasis, yet their role in maintaining neurovascular-metabolic homeostasis has not been fully explored. We hypothesized that PVM depletion compromises cerebrospinal fluid-interstitial fluid exchange through glymphatic system (GS) dysfunction, thereby exacerbating cortical hyperexcitability manifested as increased epilepsy susceptibility and seizure intensity. Using clodronate liposomes (CLOs), we achieved >85% PVM depletion in mice. Following pentylenetetrazole (PTZ) challenge, PVM-depleted mice exhibited anxiety-like behaviors (reduced center time, p < 0.05), impaired working memory (decreased spontaneous alternation, p < 0.05), and increased cortical hyperexcitability, including shorter seizure latency and elevated EEG total power (p < 0.05). Mechanistically, PVM loss led to dysregulation of extracellular matrix components (increased laminin and collagen IV), impairing perivascular space integrity and GS function (reduced CSF tracer clearance, p < 0.05). AQP4 inhibition with TGN-020 further exacerbated PTZ-induced EEG abnormalities (increased total power, p < 0.05). Analysis of human epileptic tissue confirmed elevated collagen IV deposition in the seizure focus (p < 0.05) and a trend toward increased PVM density (p = 0.0638). These results highlight PVMs as essential modulators of the glymphatic-metabolic axis, linking vascular health to brain excitability. Targeting the PVM-GS interface offers therapeutic potential for disorders involving vascular dysfunction and neuronal hyperexcitability.

• Publication year

  2026

• Venue

  Journal of Cerebral Blood Flow and Metabolism

• Publication date

  2026-02-08

• Fields of study

  Medicine

• Identifiers
  DOI 10.1177/0271678X261415782PMID 41656603PMCID PMC12885963
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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