Alexandre Bonnin, PhD

Main projects:

The major goal of my research is to identify molecular and cellular mechanisms by which prenatal insults influence normal brain development leading to neurological disorders emerging later in life. Our recent approaches explore vastly understudied mechanisms linking blood-brain barrier (BBB) formation to neurodevelopment.

A hallmark of gestational maternal immune activation is the chronic activation of microglial cells and neuroinflammation in the brain of adult offspring. These phenotypes are also observed after blood-brain barrier (BBB) lesions in adults. We recently demonstrated that gestational maternal immune activation directly impacts BBB development in utero and function across the lifespan, leading to chronic neuroinflammation and altered brain function (a). The cellular and molecular mechanisms by which prenatal inflammation and subsequent activation of the microglia in early life disrupt BBB formation, leading to barrier breakdown across the lifespan are under investigation in the lab. We are also testing if this self-perpetuating cycle of BBB breakdown and brain inflammation ultimately promotes increased risk for aging-related neuropathology later in life. We are investigating these novel mechanisms using in vivo, in vitro, a unique ex vivo organ perfusion system, as well as pharmacological, genetic and imaging tools.

Our approaches explore the vastly understudied life-long mechanisms involved in the etiology of vascular contributions to neurological disorders, and provide insights into the developmental origins of devastating diseases such as schizophrenia or neurodegenerative diseases with unclear genetic causes. Furthermore, the research will advance our understanding of the short- and long-term consequences of inflammation on the development and function of the BBB over the lifespan.

Collaborative studies of maternal vs placental influences on fetal brain development:

Our technological development of the ex vivo perfusion of the mouse placenta has led to numerous collaborative projects aiming at assessing directly the contributions of various maternally vs. placentally derived molecules to fetal brain development. For instance, this technology was applied in a collaborative project with Gerard Karsenty, MD, PhD at Columbia University, to demonstrate the maternal-fetal transfer of osteocalcin, an important neurogenic molecule, which is synthesized by maternal bone (b). It was also used in a collaboration with Robert Schwarcz, PhD, at the University of Maryland, to investigate the developmental sources of kynurenine—a branch of tryptophan metabolism, also involved in immune regulation of placental function—and its metabolites (c). It was also used in a collaboration with Tracy L. Bale, PhD, at the University of Colorado to study the effects of stress on maternally and placentally derived steroid hormones reaching the developing fetus.

a. Zhao, Q., Dai, W., Chen, H. Y., Jacobs, R. E., Zlokovic, B. V., Lund, B. T., Montagne, A., and Bonnin, A. (2022). Prenatal disruption of blood-brain barrier formation via cyclooxygenase activation leads to lifelong brain inflammation. Proc Natl Acad Sci USA 119, doi: 10.1073/pnas.2113310119. PMID: 35377817.

b. Oury F, Khrimian L, Gardin A, Chamouni A, Goeden N, Huang Y, Srinivas P, Gao X, Suyama S, Mann JJ, Horvath T, Bonnin A, Karsenty G. (2013) Maternal and offspring-derived osteocalcin influences brain development and functions. Cell 155(1), 228-41. doi: 10.1016/j.cell.2013.08.042. PMID: 24074871.

c. Goeden N, Notarangelo FM, Pocivavsek A, Beggiato S, Bonnin A, Schwarcz R (2017) Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid. Dev Neurosci, 39:519–528. doi: 10.1159/000481168. PMID: 29080891.