Conference Agenda

Bile acids are molecules synthesized in the liver from cholesterol that exert a key role in the digestion of dietary lipids. Bile acids also circulate in the blood. These molecules can therefore activate specific receptors called TGR5, which are expressed by peripheral organs, and directly modulate thermogenesis at the level of adipose tissue, for instance, facilitating weight loss. Beyond this action at peripheral organs, our work shows that circulating bile acids can also reach the hypothalamus, a brain structure that is critical for the regulation of food intake, body weight and whole-body metabolism (1, 2). The hypothalamus also expresses TGR5 receptors. In obese mice, the hypothalamic bile acid detection system by TGR5 is defective and pharmacological activation of brain TGR5 receptors leads to a decrease in body weight and fat mass. These metabolic benefits are due to an increase in the activity of the sympathetic nervous system that in turn increases energy expenditure. On the contrary, inhibition of TGR5 receptor expression and activity in neurons of the hypothalamus facilitates the development and progression of obesity. Altogether, the evidence we provide suggests that the hypothalamic bile acids-TGR5 signaling protects from obesity (1). Further underlying mechanisms and relationship with neuro-hormonal axes remain to be established.

1. Castellanos-Jankiewicz A et al., Cell Metab 2021 ; 33(7):1483-1492.e10.

2. Perino A et al., Nat Metab. 2021 ; 3(5):595-603.

Gonadotropin-releasing hormones (GnRH) neurons are the master regulators of fertility in vertebrates. GnRHneurons release their hormone through the median eminence into the hypophyseal portal system to stimulate the production and release of gonadotropins, which regulate the development and function of the gonads and ensure reproductive success.

Combining mouse genetics with Cre-dependent viral tracing approaches, 3D-imaging of whole-mouse heads, with chemogenetic and pharmacological approaches, we have identified a novel role of GnRH neurons in olfactory and cognitive functions, respectively. Finally, preclinical and clinical intervention strategies suggest that pulsatile GnRH therapy holds promise to improve cognitive deficits in human diseases.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism. It is due to the silencing of the FMR1 gene coding for an RNA-binding protein the Fragile X Messenger RibonucleoProtein (FMRP). This protein is part of ribonucleoprotein complexes associated to polyribosomes and involved in translational regulation. FMRP works mainly as a repressor of translation, but in some cases can also enhance translation. By its action, FMRP modulates the expression levels of a large subset of synaptic proteins. To date no specific treatment is available for this disorder.

During the last year, we used different and complementary approaches to identify new effective treatment for FXS. We searched for target mRNAs of FMRP by a CLIP (Cross-Link UV Immunoprecipitation) assay in brain cortex and hippocampus during synaptogenesis. Among the targets we identified, we focused our attention on those involved in the homeostasis of cAMP and cGMP and in the homeostasis of Ca²⁺. Indeed, pharmacological or genetic modulation of these pathways improves socio-cognitive behavior of the Fmr1-KO mouse.

In parallel, we established a stable shFmr1 embryonic stem cell (ES) line depleted of FMRP. Differentiation of shFmr1 ES cells into the neuronal lineage results into altered neurogenesis. Those cells display abnormal levels of molecular markers, such as B-III tubulin, p27^kip1, NeuN and NeuroD1, that were also confirmed in Fmr1-KO mouse embryonal brains at E12.5 and E14.5. We used this cell line to screen a library of biomolecules, anticipating that the molecules revealing an ability to actively revert the phenotype of this cell model would likely be candidates for pharmacological treatment of FXS. We found 4 molecules, called SM1-SM4 and we will present their positive impact on in vitro, ex-vivo and in-vivo FXS phenotypes, thus validating our second approach in the search for FXS treatment.

The Bosch-Boonstra-Schaaf optic atrophy-intellectual syndrome (BBSOAS; OMIN#615722), is a rare neurodevelopmental disorder caused by mutations in the NR2F1 gene, also known as COUP-TFI, a transcriptional regulator playing pleiotropic functions in brain development. Most NR2F1 pathological variants described so far are deletions and/or mutations leading to haploinsufficiency or dominant negative effects. Although BBSOAS is characterized by a complex and wide array of clinical features, intellectual disability (ID) associated with global developmental delay, visual impairment, and autism spectrum disorder (ASD) are the most common ones. Interestingly, NR2F1 is considered a risk gene for ASD (SFARI database), opening up new interesting perspectives on whether and how NR2F1 might be involved in the pathogenesis of ASD and related disorders.

Alterations in postnatal hippocampal neurogenesis have been reported in animal models of ASD/ID and recent findings suggest that a deficit in hippocampal plasticity may contribute to BBSOAS. Here, to investigate the possible effects of Nr2f1 haploinsufficiency on the hippocampal circuit, we took advantage of constitutive Nr2f1 heterozygous mice (i.e., Nr2f1-HET), a recently validated BBSOAS mouse model, and focussed on the adult dentate gyrus (DG), which plays key roles in cognitive processes (e.g., learning and memory).

Our in situ analyses on the DG of Nr2f1-HET hippocampi revealed morphological alterations in adult-born immature neurons with phenotypes typical of pathological conditions and aberrant hippocampal circuitry activation. Moreover we found increased expression of immediate early genes (e.g., Npas4, c-fos) and reduced frequency in mini inhibitory postsynaptic currents (mIPSCs) paralleled by decreased density of inhibitory synapses. We are currently addressing possible alterations in the excitatory synapses and trying to dissect the cell-autonomous versus non-cell-autonomous mechanisms underlying the observed phenotype.