Alexandre Bonnin, PhD

A. Main projects:
Research in the Bonnin’s lab focuses on understanding how maternal-fetal interactions shape fetal brain development during pregnancy; the goal is to identify molecular and cellular mechanism by which prenatal insults influence normal brain development leading to the emergence of mental disorders later in the offspring life.
Our two main projects aim at understanding the mechanisms by which prenatal stress and maternal immune activation (MIA), such as in response to viral infection, affect fetal brain development; two prenatal insults that are known risk factors for neurological disorders later in the offspring life.

A hallmark of gestational MIA is the chronic activation of microglial cells and neuroinflammation in the adult offspring brain. These are phenotypes also observed after blood-brain barrier (BBB) lesions in adults. We recently demonstrated that gestational MIA directly impacts BBB development in utero and BBB function across the lifespan, leading to chronic neuroinflammation and altered brain function (a). These observations support the idea that prenatal inflammation and subsequent activation of the microglia in early life disrupts BBB formation, leading to BBB breakdown across the lifespan. This self-perpetuating cycle of BBB breakdown and brain inflammation would ultimately promote increased risk for aging-related neuropathology later in life. We currently investigate this novel mechanism using pharmacological and genetic tools.
Our approaches explore vastly understudied life-long mechanisms involved in the etiology of vascular contributions to cognitive impairment and dementia, providing insights into the developmental origins of devastating diseases such as Alzheimer’s disease. 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.

B. 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 directly assessing the contributions of various maternally vs placentally-derived molecules to fetal brain development. For instance, this technology was applied in a collaborative project with Dr Karsenty (Columbia University) to demonstrate the maternal-fetal transfer of an important neurogenic molecule, osteocalcin, which is synthesized by maternal bone (b). It was also used in a collaboration with Dr Schwarcz (University of Maryland) to investigate the developmental sources of kynurenine and its metabolites (a branch of tryptophan metabolism, also involved in immune regulation of placental function) (c). It was also used in a collaboration with Dr Bale (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 U S A 119, e2113310119.

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. PMCID: PMC3864001

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.

• Brain & Behavior Research Foundation (NARSAD): Daniel X. Freedman Award for outstanding basic research achievement, 2011

• Editorial: Advances and perspectives in neuroplacentology Front Endocrinol (Lausanne). 2023; 14:1206072. . View in PubMed
• Prenatal disruption of blood-brain barrier formation via cyclooxygenase activation leads to lifelong brain inflammation Proc Natl Acad Sci U S A. 2022 04 12; 119(15):e2113310119. . View in PubMed
• In utero exposure to maternal anti-aquaporin-4 antibodies alters brain vasculature and neural dynamics in male mouse offspring Sci Transl Med. 2022 04 20; 14(641):eabe9726. . View in PubMed
• Correction to “In Utero Exposure to Citalopram Mitigates Maternal Stress Effects on Fetal Brain Development” ACS Chem Neurosci. 2020 Feb 05; 11(3):484. . View in PubMed
• Serotonin homeostasis in the materno-foetal interface at term: Role of transporters (SERT/SLC6A4 and OCT3/SLC22A3) and monoamine oxidase A (MAO-A) in uptake and degradation of serotonin by human and rat term placenta Acta Physiol (Oxf). 2020 08; 229(4):e13478. . View in PubMed
• In Utero Exposure to Citalopram Mitigates Maternal Stress Effects on Fetal Brain Development ACS Chem Neurosci. 2019 07 17; 10(7):3307-3317. . View in PubMed
• Long term effects of neonatal exposure to fluoxetine on energy balance: A systematic review of experimental studies Eur J Pharmacol. 2018 Aug 15; 833:298-306. . View in PubMed
• Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy Nat Microbiol. 2017 Nov; 2(11):1558-1570. . View in PubMed
• Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment Neuropsychopharmacology. 2017 01; 42(2):427-436. . View in PubMed
• A Placenta-Specific Genetic Manipulation Reprograms Offspring Brain Development and Function Biol Psychiatry. 2017 07 15; 82(2):81-82. . View in PubMed
• Effect of Maternal ±Citalopram Exposure on P11 Expression and Neurogenesis in the Mouse Fetal Brain ACS Chem Neurosci. 2017 05 17; 8(5):1019-1025. . View in PubMed
• Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid Dev Neurosci. 2017; 39(6):519-528. . View in PubMed
• Maternal Pharmacokinetics and Fetal Disposition of (±)-Citalopram during Mouse Pregnancy ACS Chem Neurosci. 2016 Mar 16; 7(3):327-38. . View in PubMed
• Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain J Neurosci. 2016 06 01; 36(22):6041-9. . View in PubMed
• Maternal and offspring pools of osteocalcin influence brain development and functions Cell. 2013 Sep 26; 155(1):228-41. . View in PubMed
• Ex vivo perfusion of mid-to-late-gestation mouse placenta for maternal-fetal interaction studies during pregnancy Nat Protoc. 2013 Jan; 8(1):66-74. . View in PubMed
• Placental serotonin: implications for the developmental effects of SSRIs and maternal depression Front Cell Neurosci. 2013; 7:47. . View in PubMed
• The SSRI citalopram affects fetal thalamic axon responsiveness to netrin-1 in vitro independently of SERT antagonism Neuropsychopharmacology. 2012 Jul; 37(8):1879-84. . View in PubMed
• Insights into the complex influence of 5-HT signaling on thalamocortical axonal system development Eur J Neurosci. 2012 May; 35(10):1563-72. . View in PubMed
• Placental source for 5-HT that tunes fetal brain development Neuropsychopharmacology. 2012 Jan; 37(1):299-300. . View in PubMed
• Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain Neuroscience. 2011 Dec 01; 197:1-7. . View in PubMed
• A transient placental source of serotonin for the fetal forebrain Nature. 2011 Apr 21; 472(7343):347-50. . View in PubMed
• Serotonin modulates the response of embryonic thalamocortical axons to netrin-1 Nat Neurosci. 2007 May; 10(5):588-97. . View in PubMed
• Region- and age-specific deficits in gamma-aminobutyric acidergic neuron development in the telencephalon of the uPAR(-/-) mouse J Comp Neurol. 2005 Sep 05; 489(4):449-66. . View in PubMed
• Molecular signals regulating proliferation of stem and progenitor cells in mouse olfactory epithelium Dev Neurosci. 2004 Mar-Aug; 26(2-4):166-80. . View in PubMed

• Levitt, Pat
• Zlokovic, Berislav
• Shih, Jean
• Chatzi, Vaia
• Peterson, Bradley
• Chmait, Ramen