Maternal obesity and developmental programming of neuropsychiatric disorders: An inflammatory hypothesis

Abstract

Maternal obesity is associated with the development of a variety of neuropsychiatric disorders; however, the mechanisms behind this association are not fully understood. Comparison between maternal immune activation and maternal obesity reveals similarities in associated impairments and maternal cytokine profile. Here, we present a summary of recent evidence describing how inflammatory processes contribute towards the development of neuropsychiatric disorders in the offspring of obese mothers. This includes discussion on how maternal cytokine levels, fatty acids and placental inflammation may interact with foetal neurodevelopment through changes to microglial behaviour and epigenetic modification. We also propose an exosome-mediated mechanism for the disruption of brain development under maternal obesity and discuss potential intervention strategies.

Keywords: Maternal obesity; fatty acids; inflammation; microglia; neurodevelopment; neuropsychiatric disorders; placenta.

Figure 1.

Early stages of pregnancy. After formation of the zygote upon fusion of the oocyte with a sperm cell, the zygote undergoes several rounds of cell division to form a blastocyst – a trophoblast cell layer surrounding an inner cell mass and cavity. Inner cell mass adjacent trophoblast cells interact with the uterine endometrium. Implantation follows with the breakdown of endometrial cells and endometrial invasion. Trophoblast cells continue to divide forming cytotrophoblast and syncytiotrophoblast cells of the foetal placenta. Red lightning symbols indicate key events which may be affected by maternal obesity or maternal immune activation.

Box 1.

Microglia’s developmental roles and how they are affected by maternal immune activation. Maternal obesity primes microglia’s response to activation and is hypothesised to interfere with microglia’s developmental functions. Some of the key functions of microglia’s role during brain development and the impact of immune activation are illustrated above. Upon interaction with pathogen-associated molecular patterns, microglia become activated and increase expression of interleukin (IL)-1β, IL-6 and tumour necrosis factor-α (TNF-α). Postnatal cerebellar microglia show increased proliferation and phagocytosis and become ameboid in morphology upon LPS stimulation (a). Microglia’s developmental function starts early in the brain where they regulate neural progenitor cell population size likely through increased phagocytosis (b). Prenatal microglia are thought to regulate cortical interneuron migration. Microglia invade the developing cortical plate at the same time as Lhx6 interneurons which accumulate in layer V. Maternal immune activation induces premature migration of Lhx6-expressing interneurons into the cortical plate and reduced interneuron accumulation at layer V (c). Microglia associate closely with a subset of axonal tracts and play a critical role in their development. In the corpus callosum, both MIA and microglial depletion result in axon tract defasciculation (d). By contrast, MIA reduced the extension of dopaminergic axons into the subpallium, an effect opposite to microglial depletion (e). During postnatal development, microglia remove pre-synaptic structures through trogocytosis and induce spine head formation upon contact (f). They also support survival of postnatal layer V neurons through insulin-like growth factor 1 (IGF-1) signalling and induce apotosis in postnatal cerebellar neurons (g). Similar trophic support for oligodendrocyte precursor survival and differentiation has been proposed within the postnatal corpus callosum (h). Finally, immune activation increased microglial vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor BB (PDGF-BB) expression and induced angiogenesis in retinal endothelial cells (i). CP: cortical plate; MZ: marginal zone; IZ: intermediate zone; V: layer V.

Figure 2.

Proposed mechanism for exosome-mediated microglia activation in maternal obesity. Adipocytes release pro-inflammatory exosomes (in grey) able to signal local macrophages (in pink) to become pro-inflammatory (in red). These exosomes enter maternal circulation and are able to cross the placenta into foetal circulation. Microglia (in green) are suspected to become pro-inflammatory upon interaction with maternal adipocyte–derived exosomes, interfering with microglia’s developmental roles.