Fragile X syndrome

Brain circuits in mouse pups develop and mature extensively during the first few weeks of life. During early postnatal development, sensory cortices experience patterned spontaneous activity which is known to refine neural connectivity, preparing the animal to engage in sensorimotor tasks immediately upon ear and eye opening (∼P4 and ∼P15, respectively). In primary visual cortex (V1), spontaneous activity originates from two sources, from the retina relayed by thalamus and intrinsically generated in the cortex. Spontaneous events from these two sources have different spatiotemporal properties:

Fragile X Syndrome (FXS), a frequent form of inherited intellectual disability and a leading monogenic cause of autism, is caused by lack/reduction of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in several aspects of RNA metabolism. Abnormal expression of proteins at synapses underlies brain dysfunction in FXS. FMRP is also implicated in DNA damage response and is a component of stress granules (SGs), cytoplasmatic aggregates that form in response to stress and are protective against apoptosis. Evidence in the mouse model of FXS suggests an excess of oxidizing

Fragile X Syndrome (FXS), the most common hereditary cause of intellectual disability and autism spectrum disorder, is caused by the lack of expression of the Fragile X messenger ribonucleoprotein 1 (FMRP). FMRP is a widely expressed RNA-binding protein that plays a pivotal role in regulating protein synthesis. The absence of its expression has been linked to abnormal synaptic transmission and improper dendritic spines morphogenesis, which are tough to underlies the bulk of the cognitive and behavioral defects exhibited by FXS patients. However, our current understanding of FXS physiopathology

…(OL) development and myelination in Fragile X syndrome (FXS), a NDD caused by the

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by expansion mutation in the FMR1 gene, which leads to gene silencing via imprinting. Fmr1, located on the X chromosome, encodes the protein FMRP, a pivotal protein for neurogenesis in cortical development (Saffary and Xie, 2011; Casingal et al., 2020). Interestingly, female FXS premutation carriers, especially those with a paternal lineage of the premutation, exhibit an increased incidence of premature ovarian failure (Hundscheid et al., 2000). Despite these findings, the impact of FMRP absence on imprinting mechanisms in the br

Fragile X Syndrome (FXS) is the most common neurodevelopmental disorder associated with intellectual disabilities. In FXS, an increased CGG triplet repetition in the fmr1 gene, cause the hypermethylation of the 5’UTR and, in turn leads to the gene silencing and the absence of the Fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein, able to regulate the expression of different RNAs and fundamental for synapses function. FMRP is expressed in neurons but also in astrocytes and microglia, the other key cells of the brain. Despite many studies have focused their attentions o

Repetitive stereotyped behaviors are core symptoms of autism spectrum disorders (ASD) and fragile X syndrome (FXS), the prevalent genetic cause of intellectual disability and autism. The nigrostriatal dopamine (DA) circuit is key to movement control and creation of habits and sequential behaviors, thus its dysregulation could promote occurrence of autistic repetitive behaviors. However, specific evidence proving altered nigral DA neuron activity in ASD or FXS models is absent. In this study, by analyzing nigral DA neuron activity in adolescent Fmr1 KO mice by ex vivo electrophysiology we provi

…and mTOR hyperactivity-associated Fragile X Syndrome (FXS), both characterized by severe cognitive dysfunctions. On the other hand, medial Temporal Lobe Epilepsy (mTLE) is associated with mTOR hyperactivity within the hippocampal formation and cognitive deficits, particularly pertaining to pattern separation and episodic memory. The hippocampal dentate gyrus (DG) subregion is crucial for gating the flow and separating the patterns of cortical information inputs, transmitting them via DG granule cell mossy

Fragile X syndrome (FXS) is the most common inherited form of Intellectual Disability and a leading monogenic cause of autism. FXS results from mutations within the FMR1 gene causing the loss-of-function of the RNA-binding Fragile X Messenger RibonucleoProtein (FMRP). FMRP transports mRNAs along dendrites toward the base of active synapses for their activity-dependent translation. In FXS, the loss-of-function of FMRP leads to a hyper-abundance of dendritic protrusions. Several FMR1 missense mutations identified in patients also lead FXS but how these mutations affect the function of FMRP and l

Fragile X Syndrome (FXS) is a neurodevelopmental disorder that can cause impairments in spatial cognition. The hippocampus is thought to support spatial cognitive functions through the activity of place cells, neurons with spatial receptive fields. The reactivation or “replay” of previously active place cell sequences during sharp wave-ripples (SWRs) is believed to be important for spatial memory-guided planning and spatial memory consolidation. Previous research has shown that SWRs are abnormal in a mouse model of FXS (Boone et al. 2018), but to our knowledge the replay of place cell sequence

…Fragile X Syndrome (FXS) is a neurodevelopmental disorder associated with abnormal social behaviors. To our knowledge, the activity of CA2 place cells during social interactions has not been examined in relation to FXS. Here, we recorded CA2 place cells in wildtype (WT) c

Impaired social interaction is a core dimension of developmental disorders, including Fragile X Syndrome (FXS). The mouse model of FXS displays abnormal sociability and our research shows that maternal Fmr1 deficiency is sufficient to induce this phenotype. Specifically, maternal Fmr1 haploinsufficiency induces hypersociability in her wild-type (WT) male offspring, indicating developmental sensitivity to maternal FMRP levels. Oxytocin (OXT) release in the ventral tegmental area (VTA) mediates dopamine neuron activity, whose projections to the nucleus accumbens bidirectionally modulate duration

Group I metabotropic glutamate receptors (mGluR) are involved in various forms of synaptic plasticity that underlie declarative memory by inducing long-term depression (mGluR-LTD). mGLUR-LTD results from an endocytosis of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) underlying synaptic depression. The lab has previously shown that mGluR5 specifically activates TRPC1 channel, a Transient Receptor Potential channel that is highly expressed in CA1-3 regions of the hippocampus.To investigate the role of mGluR-TRPC1 in synaptic plasticity, and to decipher its downstre

Exaggerated responses to sensory stimuli is a hallmark of Fragile X syndrome (FXS), contributes to, inattention, anxiety, and learning challenges. Such sensory hypersensitivity are recapitulated in the Fmr1 knockout (KO). Recent studies in Fmr1 KO mice have demonstrated differences in GABAergic inhibition, including activity of cortical interneurons as well as a delayed switch in the polarity of GABA signaling during development. Previously, we found that administration of bumetanide to block the chloride (Cl-) transporter NKCC1, could rescue synaptic circuit phenotypes in primary somatosensor

Fragile X syndrome (FXS), is the most common monogenetic cause of mental impairment and autistic traits. Symptoms in people with FXS include auditory hypersensitivity and communication problem, which is recapitulated in the FXS mouse model. Previous studies in FXS mice showed only moderate increased neural activity levels in different parts of the ascending auditory pathways in response to simple tones. Here we characterized whether complex sounds with a behavioural relevance, such as vocalizations, evoke neural activity patterns that differ between FXS KO and WT mice. We used playback of low-

Fragile X syndrome is the most common form of inherited intellectual disability and a major cause of autism spectrum disorder. This syndrome is caused by the silencing of the Fmr1 gene, which codes for the RNA-binding protein, FMRP. Most studies have focused on dendritic and postsynaptic mechanisms. Here we aim at characterising the functional involvement of new FMRP targets by exploring the consequences of FMRP loss on presynaptic mechanisms. We focus in particular on a recently identified target, Phosphodiesterase 2A (PDE2A). PDE2A is located in the presynaptic compartment and is highly expr

Fragile X syndrome (FXS), caused by inactivation of Fmr1 gene, is the most common cause of intellectual disability and autism spectrum disorder. Fmr1 knockout (Fmr1KO) mice display a disorganization of perineuronal nets (PNNs), specialized forms of extracellular matrix which form around neurons during postnatal development in many brain areas. These nets are preferentially established around Parvalbumin-positive GABAergic interneurons (PVIs), and their presence reduces brain plasticity. PNN and PVI expression is altered in various neuropsychiatric disorders and in some cases their manipulation

Individuals afflicted with certain types of autism spectrum disorder often exhibit impaired cognitive function alongside enhanced emotional symptoms and mood lability. However, current understanding of the pathogenesis of autism and intellectual disabilities is based primarily on studies in the hippocampus and cortex, brain areas involved in cognitive function. But, these disorders are also associated with strong emotional symptoms, which are likely to involve changes in the amygdala and other brain areas. In this talk I will highlight these issues by presenting analyses in rat models of ASD/I

Silencing of FMR1 and loss of its gene product, FMRP, results in fragile X syndrome (FXS). FMRP binds brain mRNAs and inhibits polypeptide elongation. Using ribosome profiling of the hippocampus, we find that ribosome footprint levels in Fmr1-deficient tissue mostly reflect changes in RNA abundance. Profiling over a time course of ribosome runoff in wild-type tissue reveals a wide range of ribosome translocation rates; on many mRNAs, the ribosomes are stalled. Sucrose gradient ultracentrifugation of hippocampal slices after ribosome runoff reveals that FMRP co-sediments with stalled ribosomes,

…approach in theFmr1-/- mouse model of Fragile X syndrome (FXS). Using a go/no-go task and in vivo 2-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons in primary visual cortex, and a decrease in the activity of parvalbumin (PV) interneurons. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was s

Despite the consistency of symptoms at the cognitive level, we now know that brain disorders like Autism and Schizophrenia can each arise from mutations in >100 different genes. Presumably there is a convergence of “symptoms” at the level of neural circuits in diagnosed individuals. In this talk I will argue that redundancy in neural circuit parameters implies that we should take a circuit-function rather that circuit-component approach to understanding these disorders. Then I will present our recent empirical work testing a circuit-function theory for Autism: the idea that neural circuits sho