Biology subjects

De Felice, A.

Publications and source records attributed to De Felice, A..

4 recordsLinked to original sources

bioRxiv2022

Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral and transcriptomic levels

Many neurodevelopmental conditions, including autism, affect males more than females. Genomic mechanisms enhancing risk in males may contribute to this sex-bias. The ubiquitin protein ligase E3A gene (Ube3a) exerts pleiotropic effects on cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal region 15q11-13 causes 1-2% of autistic cases. Here, we test the hypothesis that increased dosage of Ube3a may influence autism-relevant phenotypes in a sex-biased manner. We report robust sex-biasing effects on brain connectomics and repetitive behaviors in mice with extra copies of Ube3a. These effects were associated with a profound transcriptional dysregulation of several known autism-associated genes (e.g., FMR1, SCN2A, PTEN, MEF2C, SHANK3, TSC2) as well as differentially-expressed genes identified in human 15q duplication and in autistic patients. Notably, increased Ube3a dosage also affects multiple sex-relevant mechanisms, including genes on the X chromosome, genes influenced by sex steroid hormones, downstream targets of the androgen and estrogen receptors, or genes that are sex-differentially regulated by transcription factors. These results suggest that Ube3a overdosage can critically contribute to sex-bias in neurodevelopmental conditions via influence on sex-differential mechanisms.

neuroscience↗

bioRxiv2020

A cross-species link between mTOR-related synaptic pathology and functional hyperconnectivityin autism

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism, with a putative link to aberrant mTOR-dependent synaptic pruning. Autism is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses cause aberrant functional connectivity in autism. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with autism-like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic autism exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for autism-dysregulated genes interacting with mTOR or TSC2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism. SignificanceAberrant brain functional connectivity is a hallmark of autism, but the neural basis of this phenomenon remains unclear. We show that a mouse line recapitulating mTOR-dependent synaptic pruning deficits observed in postmortem autistic brains exhibits widespread functional hyperconnectivity. Importantly, pharmacological normalization of mTOR signalling completely rescues synaptic, behavioral and functional connectivity deficits. We also show that a similar connectivity fingerprint can be isolated in human fMRI scans of people with autism, where it is linked to over-expression of mTOR-related genes. Our results reveal a unifying multi-scale translational framework that mechanistically links aberrations in synaptic pruning with functional hyperconnectivity in autism.

neuroscience↗

bioRxiv2019

Acute and repeated intranasal oxytocin differentially modulate brain-wide functional connectivity

Central release of the neuropeptide oxytocin (OXT) modulates neural substrates involved in socio-affective behavior. This property has prompted research into the use of intranasal OXT administration as an adjunctive therapy for brain conditions characterized by social impairment, such as autism spectrum disorders (ASD). However, the neural circuitry and brain-wide functional networks recruited by intranasal OXT administration remain elusive. Moreover, little is known of the neuroadaptive cascade triggered by long-term administration of this peptide at the network level. To address these questions, we applied fMRI-based circuit mapping in adult mice upon acute and repeated (seven-day) intranasal dosing of OXT. We report that acute and chronic OXT administration elicit comparable fMRI activity as assessed with cerebral blood volume mapping, but entail largely different patterns of brain-wide functional connectivity. Specifically, acute OXT administration focally boosted connectivity within key limbic components of the rodent social brain, whereas repeated dosing led to a prominent and widespread increase in functional connectivity, involving a strong coupling between the amygdala and extended cortical territories. Importantly, this connectional reconfiguration was accompanied by a paradoxical reduction in social interaction and communication in wild-type mice. Our results identify the network substrates engaged by exogenous OXT administration, and show that repeated OXT dosing leads to a substantial reconfiguration of brain-wide connectivity, entailing an aberrant functional coupling between cortico-limbic structures involved in socio-communicative and affective functions. Such divergent patterns of network connectivity might contribute to discrepant clinical findings involving acute or long-term OXT dosing in clinical populations.

neuroscience↗

bioRxiv2017

Serotonin Buffers Hippocampal Neuroplasticity And Emotional Behavior

Adaptation to environmental insults is an evolutionary mechanism essential for survival. The hippocampus participates in controlling adaptive responses to stress and emotional state through the modulation of neuroplasticity events, which are dysregulated in stress-related neuropsychiatric disorders. The neurotransmitter serotonin (5-HT) has been proposed as a pivotal player in hippocampal neuroplasticity in both normal and neuropsychiatric conditions though its role remains still poorly understood. Here, we investigated the impact of 5-HT deficiency on hippocampal activity combining RNA-seq, in vivo neuroimaging, neuroanatomical, biochemical and behavioral experiments on 5-HT depleted mice. We unveil that serotonin is required for appropriate activation of neuroplasticity adaptive mechanisms to environmental insults. Bidirectional deregulation of these programs in serotonin depleted mice is associated with opposite behavioral traits that model core symptoms of bipolar disorder. These findings delineate a previously unreported buffering role of 5-HT in instructing hippocampal activity and emotional responses to environmental demands.

neuroscience↗