Lysophosphatidic acid (LPA)-dependent propagation of neuroinflammation in an optimized model of post-hemorrhagic hydrocephalus.

Post-hemorrhagic hydrocephalus (PHH) is a neurological disease that primarily affects premature infants and involves infiltration of blood into the brain’s ventricles followed by excessive accumulation of cerebrospinal fluid (CSF) leading to ventricular enlargement and increased intracranial pressure. However, the precise mechanisms driving PHH development and persistence remain incompletely known and lack medical and disease modifying treatments. Here we use a mouse model of PHH to identify transcriptomic, proteomic and cellular changes involving neurovascular and neuroimmunological microglial alterations as features of PHH, overlapping with those reported in human disease. Improvements on a lysophosphatidic acid (LPA)-initiated PHH mouse model were developed and combined with unbiased proteomic and single-nucleus transcriptomics that identified microglial molecular pathways promoting PHH. Pharmacological disruption of microglia in vivo significantly reduced PHH-associated ventriculomegaly. These data identify microglia and neurovascular molecular elements in the development of PHH, implicating them as potentially tractable therapeutic targets towards developing new treatments for PHH.