Prenatal inflammation disrupts blood-brain barrier development and long-term function

SUMMARY
Maternal immune activation (MIA) during fetal development increases risk for neurodevelopmental disorders
(NDDs) later in the offspring life. Chronic microglial activation in the adult offspring exposed to gestational MIA
leads to a range of altered behaviors. Yet, the developmental mechanisms whereby MIA induces this sustained
activation of offspring brain microglia across the lifespan are not understood. Systemic inflammation triggered
during adulthood was shown to disrupt blood-brain barrier (BBB) function, inducing microglial activation,
neuroinflammation and leading to the progressive emergence of neuropathologies. Even though comparable
outcomes are observed in adult offspring who experienced gestational MIA, whether there is similar BBB
disruption and the mechanisms leading to these phenotypes in utero are not known. This is an important
knowledge gap because MIA is a risk factor for NNDs and there is growing evidence of vascular dysfunction
contributing to the molecular pathology of these disorders.
The investigators obtained preliminary data showing that MIA triggered by the viral mimetic poly(I:C) in pregnant
mice disrupts fetal BBB formation leading to increased nascent BBB permeability measured using live fetal MRI.
Their data further suggest that activation of the cyclooxygenase-2 (COX2; Ptgs2) pathway in fetal brain microglia
is causal to MIA effects. Importantly, longitudinal MRI analyses suggest that disruption of fetal BBB formation
induces persistent BBB hyperpermeability and life-long brain microglial activation, cerebrovascular inflammation,
and behavioral alterations in the offspring.
Through the combined expertises of four different research groups, the investigators developed and
validated new methods for measuring fetal brain BBB permeability in vivo (MRI) and ex vivo (whole fetus
perfusion) which, together with conditional knockout mouse lines, will be used to test: 1) if and how MIA activation
of the COX2 pathway in fetal microglia perturbs fetal BBB formation at a critical time of development, leading to
incomplete maturation, and 2) if and how the resulting protracted activation of COX2 pathway in resident
microglia prolongs BBB structural disruption and neuroinflammation over the offspring lifespan. This self-
perpetuating cycle of brain inflammation and BBB disruption would ultimately promote increased risk for
neuropathology in the offspring. From an etiological standpoint, this pre-clinical proposal will define novel cellular
and molecular pathways involved in life-long effects of prenatal insults, shedding light on the mechanisms by
which early inflammation is causally linked to vascular disruptions in neurodevelopmental disorders.

Grant Number: 7R01NS126981-03
NIH Institute/Center: NIH
Principal Investigator: Alexandre Bonnin