Biology subjects

Givalois, L.

Publications and source records attributed to Givalois, L..

3 recordsLinked to original sources

bioRxiv2025

Shedding light on left hippocampal mGlu5 in Alzheimer's disease

Metabotropic glutamate receptor 5 (mGlu5) plays a central role in synaptic plasticity and memory, and has emerged as a potential therapeutic target in Alzheimers disease (AD). While asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show the presence of a physiological left-right asymmetry in mGlu5 expression in the hippocampus of wild-type mice, with higher levels in the left hemisphere, consistent with previous observations. Importantly, we reveal that this asymmetry is lost in J20 AD model mice due to a selective reduction of mGlu5 in the left hippocampus. Then, using the light-controllable negative allosteric modulator Alloswitch-1, we demonstrate that selective inhibition of mGlu5 in the left, but not right, hippocampus is both necessary and sufficient to restore working and short-term memory in J20 mice. This left-specific modulation also reverses downstream pathological signaling, including aberrant Pyk2 and GSK3-{beta} activation and tau hyperphosphorylation, in both hippocampi. Our findings identify a functional lateralization of mGlu5 in hippocampal circuits and highlight the potential of spatially targeted photopharmacology for precise intervention in early AD pathology.

neuroscience↗

bioRxiv2024

A photoswitchable positive allosteric modulator to control the activation of the metabotropic glutamate receptor 5 by light

1.The metabotropic glutamate receptor 5 (mGlu5) is widely expressed in the brain, where it plays an important role in synaptic plasticity, learning and memory, making it a therapeutic target of interest in various neurological disorders. In this study, we developed a photoswitchable positive allosteric modulator (PAM) of the mGlu5, as a novel tool for this clinically relevant drug target. To that aim, we used an azologisation strategy of the mGlu5 PAM agonist VU0424465 leading to the molecule azoglurax. We observed a reversible photoisomerization of azoglurax in solution with optimal wavelengths of 365 nm and 435 nm for trans to cis and cis to trans isomerization, respectively. In cell-based assays, azoglurax potentiates the agonist-induced activity of mGlu5 with a sub-micromolar potency in the dark. This potency is reduced under UV illumination. Similar to its parent molecule, azoglurax acts as an allosteric agonist of mGlu5, activating the receptor in absence of glutamate, as demonstrated on a glutamate-insensitive mutant receptor. Docking and site-directed mutagenesis experiments also suggest that azoglurax and VU0424465 bind the same pocket. In addition, molecular dynamics on cis-azoglurax-bound mGlu5 suggests that it azoglurax cis isomer does not bind stably in the receptor, in contrast to the trans-isomer, explaining the difference of activity between the two isomers. In conclusion, azoglurax is the first mGlu5 photoswitchable PAM agonist reported to date, retaining the properties and the binding mode of its parent in the dark, while the insertion of an azobenzene confers light-regulated activity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/629646v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1e0c1f4org.highwire.dtl.DTLVardef@dd7e36org.highwire.dtl.DTLVardef@1892657org.highwire.dtl.DTLVardef@1343743_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

pharmacology and toxicology↗

bioRxiv2022

Separating the effects of sex hormones and sex chromosomes on behavior in the African pygmy mouse Mus minutoides, a species with XY female sex reversal.

In mammals, most sex differences in phenotype are controlled by gonadal hormones, but recent work on transgenic mice have shown that sex chromosomes can have a direct influence on sex-specific behaviors. In this study, we take advantage of the naturally occurring sex reversal in a mouse species, Mus minutoides, to investigate for the first time the relationship between sex chromosomes, hormones and behaviors in a wild species. In this model, a feminizing variant of the X chromosome, named X*, produces three types of females with different sex chromosome complements (XX, XX*, and X*Y), associated with alternative behavioral phenotypes, while all males are XY. We thus compared the levels of three major circulating steroid hormones (testosterone, corticosterone and estradiol) in the four sex genotypes to disentangle the influence of sex chromosomes and sex hormones on behavior. First, we did not find any difference in testosterone levels in the three female genotypes, although X*Y females are notoriously more aggressive. Second, in agreement with their lower anxiety-related behaviors, X*Y females and XY males display lower baseline corticosterone concentration than XX and XX* females. Instead of a direct hormonal influence, this result rather suggests that sex chromosomes may have an impact on the baseline corticosterone level, which in turn may influence behaviors. Third, estradiol concentrations do not explain the enhanced reproductive performance and maternal care behavior of the X*Y females compared to the XX and XX* females. Overall, this study highlights that most of the behaviors varying along with sex chromosome complement of this species are driven by genetic factors rather than steroid hormone concentrations.

evolutionary biology↗