Autism spectrum disorders

…on microglial contributions to autism spectrum disorders. The project tests how genetic alterations and prenatal immune challenges affect distinct microglial populations, neuronal maturation, circuit development and behaviour. Complementary human in vitro systems and mouse models support comparisons across developmental stage, brain region and sex. Experience in molecular and cellular research is required; iPSC-derived models, microglia–neuron cocultures, flow cytometry, imaging, animal models or bioinformatics are advantage

…circuit dynamics in a mouse model of autism (IB2 knock-out, KO), within the context of the cerebellar cortical microcircuit. In this work, we used a bottom-up approach: the microcircuit connectivity was

LNX1 and LNX2 proteins are closely related PDZ domain-containing E3 ubiquitin ligases expressed in neurons. They can interact with and potentially modulate a numerous synaptic proteins, but the in vivo physiological relevance of most of these interactions remains uncertain. We previously reported that mice lacking both LNX1 and LNX2 in the central nervous system exhibit decreased anxiety-related behaviour. Separately, abnormalities in social learning and sociability were described in a distinct LNX1 knockout mouse line. To extend this work we have examined: (1) anxiety-related behaviour in LNX

…to neuropsychological disorder such as autism spectrum disorders (ASD). HPC-1/syntaxin1A (STX1A) is known to regulate neurotransmitter release at pre-synaptic terminal. Previously, we found that some ASD patients were haploid for STX1A gene. We also reported that STX1A gene knockout mice (STX1A KO) showed unusual behavioral profiles similar to human ASD patient. Interestingly, the deficit of social recognition, one of the unusual behavior in STX1A KO, partially ameriolated with dopamine (DA) receptor agonis

Autism Spectrum Disorders (ASDs) are complex neurodevelopmental conditions characterized by deficits in social interaction, communication and cognitive flexibility. In the search of possible etiopathological mechanisms of ASDs, multiple studies linked aberrant mesolimbic reward pathway to dysfunction in sociability and restricted behaviors. However, the lateral habenula (LHb), representing the anti-reward center of the central nervous system, has been neglected so far. LHb activity encodes aversive responses and inhibits the physiological dynamics of ventral tegmental area (VTA), interfering w

As a whole, the brain interstitial system (ISS) comprises 15-20% of brain tissue providing a supporting microenvironment that nurtures neuronal and glial cells. Many of the components that make up the brain extracellular fluid are not secreted locally at the brain, but rather synthesized in peripheral organs and then imported to the nervous system via the cerebrospinal fluid (CSF) or the bloodstream. Despite the relevance of the ISS during brain development, profiling the different molecules that compose the extracellular space of the brain has proven to be a daunting task due to the complexit

Altered sensory experience is now considered a key feature of neurodevelopmental and autism spectrum disorders (ASD). This alteration results in, and often predicts, a range of cognitive, social, and behavioural affective impairments, strongly impacting the quality of life. However, the underlying neurophysiological mechanisms that disrupt sensory perception remain understudied. We investigated these mechanisms in a mouse model of SYNGAP1 haploinsufficiency (ΗΕΤ), SYNGAP1 being one of the most prevalent neurodevelopmental disorder genes. Using in vivo two-photon calcium imaging, we found that

…contribute to neurodevelopmental disorders, including autism spectrum disorders. In Niemann-Pick C1 (NPC1) disease, a lysosomal lipid accumulation disorder, cerebellar granule cells (GCs) proliferation and migration are impaired, due to reduced levels of Shh and BDNF during early postnatal development, affecting cerebellar cytoarchitecture.Since GCs complete their differentiation in early postnatal life driven by BDNF signaling, establishing synaptic con

Among the genomic alterations identified as risk factors in Autism Spectrum Disorders (ASD), haploinsufficiency of AMBRA1 (Activating Molecule in Beclin1-Regulated Autophagy) triggers an ASD phenotype associated with hippocampal hyperexcitability exclusively in the female sex. Remarkably, AMBRA1 protein is constitutively more expressed in the hippocampus of wild-type (Wt) females than males. However, being more decreased by AMBRA1 deficiency in the female than the male sex, it results comparably expressed in the hippocampus of autistic females and non-autistic males. In this study, we verified

Autism spectrum disorders (ASDs) are a range of neurodevelopmental disorders affecting social communication and behavior. Brain network dysfunctions are supported as a neurobiological basis for ASDs. Thus, functional connectivity (FC) studies are pivotal for unraveling autism-related large-scale network dynamics. Although functional imaging studies during development can be instrumental for autism diagnosis, longitudinal studies of FC consolidation over development to adulthood are missing in mice. SHANK3 is a postsynaptic scaffolding protein of excitatory synapses. Its deletion or mutation is

Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders characterized by impairments in social behavior and communication. Traditional research on the biology of ASDs has focused on the central nervous system (CNS), aiming to identify brain regions, molecular mechanisms, and genetic mutations associated with ASDs. However, an increasingly holistic approach to ASDs demonstrated that there is comorbidity with immune and gastrointestinal (GI) dysfunctions. It is now accepted that there is a bidirectional communication between the gut and the brain, with the microbiota play

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

Mitochondrial dysfunction has been detected in the brains of patients with autism spectrum disorders (ASD) with unclear mechanisms. We herein identify that G protein-coupled receptor 50 (GPR50), which harbors two variations in male ASD patients at Δ502-505 and T532A, is required in mitophagy. GPR50, which does not distribute endogenously in the mitochondrion, is recruited to the damaged mitochondrion, where it marks the mitochondrial portion and recruits the assembling autophagosomes, eventually facilitating itself with the mitochondrial fragments to the autophagosomes. The above process is as

Vitamin D has been utilized gestationally in both animal models of autism and human studies with promising efficacy. Robust meta-analyses in autism have linked the vitamin D receptor (VDR) gene, which stands out as one of the few consistently surviving meta-analyses in autism research. This suggests a potential role for vitamin D in the etiology or modulation of autism spectrum disorders. Our study aims to investigate the effects of prenatal vitamin D3 supplementation on neurodevelopmental outcomes in Wistar rat offspring. We focus on indicators of autistic-like behaviors (such as ultrasonic v

Autism spectrum disorders (ASD) are associated with a high genetic heterogeneity, yet for many of the cases, the underlying molecular causes remain elusive. While several studies have elucidated some distinct patterns, fundamental questions persist: How do mutations dispersed across numerous genes lead to the development of a phenotypically similar disorder? Essentially, it remains largely unclear whether mutations in distinct genes lead to similar molecular and cellular states within the brain. Thus, it is important to identify molecular mechanisms responsible aiming to decipher points of con

Autism Spectrum Disorders (ASD) are a range of neurodevelopmental disorders, characterized by behavioral and neuronal anomalies. Phelan-McDermid Syndrome (PMS) constitutes a specific neurodevelopmental disorder exhibiting ASD-like behaviors, caused by mutations or deletions of SHANK3 gene. Mice lacking the SHANK3 gene are widely considered a reliable model to study PMS, since they show autism-like behaviors and sensory deficits, such as aberrant whisker-dependent texture discrimination and local hyperactivation of the barrel-field cortex. These local alterations mirror dysfunctions of the enti

…synapses, including epilepsy or autism spectrum disorders (ASD). One of many genes linked to these conditions is the scaffold protein neurobeachin (NBEA), which has been previously described as essential for receptor targeting to the plasma membrane. While its role at excitatory synapses has been studied extensively, NBEA function at inhibitory synapses is still barely understood. Here we report that NBEA is recruited to the GABAergic synapses in an activity-dependent manner and interacts with t

…neurodevelopmental diseases, such as autism spectrum disorders (ASD). Our team has demonstrated a crucial role for the 5-HT6R in neurodevelopment. It participates in neuronal migration, the initiation of neurite growth and dendritic arborization, through interactions with different protein partners. We also confirmed that this receptor is mainly expressed in the primary cilium of neurons and astrocytes, except f

Neurodevelopmental disorders (NDDs) are prevalent neurodevelopmental conditions which affected 3% of general population without effective treatment so far. Among the NDD candidate genes, mutations in PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked Intellectual Disability (ID) and Autism Spectrum Disorders (ASD). The aim of the study is deciphering the molecular and cellular role of PTCHD1 in brain development and understanding its pathological impact leading to NDD.To dissect the molecular mechanisms allowing PTCHD1 receptor interactions at synapse,

Severe anxiety frequently co-occurs with core symptoms of autism spectrum disorders (ASD); however, the determinants are unexplored (Kerns et al., 2021). One of the most reliable anomalies reported in both ASD and anxiety disorder patients is an aberrant functional connectivity between the salience network and the default mode network (Uddin et al., 2015). Our data indicate that a specific inhibitory neuronal subpopulation plays a fundamental role in salience detection and in gating sensory stimuli to adaptively shape behavior. The aim of the project is to test whether failure in the encoding

…in several brain conditions, including autism spectrum disorders (ASD), Down syndrome (DS), and drug-resistant epilepsy (DRE). Interestingly, NKCC1 inhibition rescues core symptoms of these brain conditions in rodent models and/or clinical trials. However, current NKCC1 inhibitors have diuretic effects by also inhibiting the kidney Cl transporter NKCC2. These diuretic effects pose critical health conc

…a core aspect and early life marker of Autism Spectrum Disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during the juvenile or adult period. Our research concentrates on neonate mice lacking the autism-associated gene Magel2. MAGEL2 is an imprinted gene highly expressed in the hypothalamus that is paternally expressed and for which paternal deletion and point mutation cause Prader-Willi and Schaaf-Yang respectively; two syndromes with a high prevalence of

Hypoxia is increasingly seen as urgent physiological driving force, permitting cells within the brain and in other parts of the body to acclimate to lowered oxygen (O2) and reduced metabolism. The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks, provoking a relative decrease in O2 in relation to the acutely augmented requirement. We named this essential, demand-dependent drop in O2 accessibility ′functional hypoxia′. Major players within the hypoxia reaction are hypoxia-inducible factors (HIF) and associated prolyl-hydroxylases. HIF

Autism Spectrum disorders (ASD) exhibit a gender bias where boys are affected predominantly. However, the mechanisms underlying resilience in VPA females are not entirely understood. To shed light on this disparity, we utilized an ASD mouse model, the valproic acid (VPA) model where sociability is more affected in males than females. We hypothesized that immunological mechanisms are involved in the resilience of VPA female mice particularly during the juvenile period because this is when they display unique neuroinflammatory patterns. To tackle this hypothesis, we assessed the impact of juveni