Biology subjects

Bardoni, B.

Publications and source records attributed to Bardoni, B..

3 recordsLinked to original sources

bioRxiv2023

Defects in AMPAR trafficking and microglia activation underlie socio-cognitive deficits associated to decreased expression of Phosphodiesterase 2A

Phosphodiesterase 2A (PDE2A) is an enzyme involved in the homeostasis of cAMP and cGMP and is the most highly expressed PDE in human brain regions critical for socio-cognitive behavior. In cortex and hippocampus, PDE2A expression level is upregulated in Fmr1-KO mice, a model of the Fragile X Syndrome (FXS), the most common form of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Indeed, PDE2A translation is negatively modulated by FMRP, whose functional absence causes FXS. While the pharmacological inhibition of PDE2A has been associated to its pro-cognitive role in normal animals and in models of ID and ASD, homozygous PDE2A mutations have been identified in patients affected by ID, ASD and epilepsy. To clarify this apparent paradox about the role of PDE2A in brain development, we characterized here Pde2a+/- mice (homozygote animals being not viable) at the behavioral, cellular, molecular and electrophysiological levels. Pde2a+/- females display a milder form of the disorder with reduced cognitive performance in adulthood, conversely males show severe socio-cognitive deficits throughout their life. In males, these phenotypes are associated with microglia activation, elevated glutathione levels and increased externalization of GluR1 in CA1, producing reduced mGluR-dependent LTD. Overall, our results reveal molecular targets of the PDE2A-dependent pathway underlying socio-cognitive performance. These results clarify the mechanism of action of pro-cognitive drugs based on PDE2A inactivation, which have been shown to be promising therapeutic approaches for Alzheimer Disease, schizophrenia, FXS as well as other forms of ASD.

animal behavior and cognition↗

bioRxiv2020

Agonist-induced Functional Analysis and Cell Sorting, a novel tool to select and analyze neurons: Fragile X as a proof of concept.

To get a better insight into the dynamic interaction between cells and their environment, we developed the agonist-induced Functional Analysis and Cell Sorting (aiFACS) technique, which allows the simultaneous recording and sorting of cells in real-time according to their immediate and individual response to a stimulus. By modulating the aiFACS selection parameters, testing different developmental times, using various stimuli and multiplying the analysis of readouts, it is possible to analyze cell populations of any tissue, including tumors. The association of aiFACS to single-cell transcriptomic allows to build a tissue cartography based on specific functional response/s of cells. As proof of concept, we used aiFACS on the dissociated mouse brain, a highly heterogenous tissue, enriching it in interneurons upon stimulation with an agonist of the glutamate receptors and upon sorting based on calcium levels. Further single-cell RNA-seq of these aiFACS-selected interneurons resulted in a nine-cluster classification. Furthermore, we used aiFACS on interneurons derived from the brain of the Fmr1-KO mouse, a rodent model of Fragile X syndrome. We show here that these interneurons manifest a generalized defective pharmacological response compared to wild type, affecting all the analyzed cell clusters at one specific post-natal developmental time.

genomics↗

bioRxiv2020

Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense Fmr1 mutant mouse model of Fragile X syndrome

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. FXS is usually caused by a CGG-repeat expansion in the FMR1 gene leading to its silencing and the loss-of-expression of the Fragile X Mental Retardation Protein (FMRP). Missense mutations were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS in these patients, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that the Fmr1R138Q hippocampus has an increased spine density associated with postsynaptic ultrastructural defects and increased AMPA receptor surface expression. Combining biochemical assays, high-resolution imaging and electrophysiological recordings, we also show that the mutation impairs the hippocampal long-term potentiation (LTP) and leads to socio-cognitive deficits in Fmr1R138Q mice. These findings reveal that the R138Q mutation impacts the synaptic functions of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients.

neuroscience↗