Biology subjects

Matteoli, M.

Publications and source records attributed to Matteoli, M..

5 recordsLinked to original sources

bioRxiv2025

Biological subtyping of autism via cross-species fMRI

It is frequently assumed that the phenotypic heterogeneity in autism spectrum disorder reflects underlying pathobiological variation. However, direct evidence in support of this hypothesis is lacking. Here, we leverage cross-species functional neuroimaging to examine whether variability in brain functional connectivity reflects distinct biological mechanisms. We find that fMRI connectivity alterations in 20 distinct mouse models of autism (n=549 individual mice) can be clustered into two prominent hypo- and hyperconnectivity subtypes. We show that these connectivity profiles are linked to distinct signaling pathways, with hypoconnectivity being associated with synaptic dysfunction, and hyperconnectivity reflecting transcriptional and immune-related alterations. Extending these findings to humans, we identify analogous hypo- and hyperconnectivity subtypes in a large, multicenter resting state fMRI dataset of n=940 autistic and n=1036 neurotypical individuals. Remarkably, hypo- and hyperconnectivity autism subtypes are replicable across independent cohorts (accounting for 25.1% of all autism data), exhibit distinct functional network architecture, are behaviorally dissociable, and recapitulate synaptic and immune mechanisms identified in corresponding mouse subtypes. Our cross-species investigation, thus, decodes the heterogeneity of fMRI connectivity in autism into distinct pathway-specific etiologies, offering a new empirical framework for targeted subtyping of autism.

neuroscience↗

bioRxiv2022

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and excitability. Genes related to neuronal transmission chiefly followed 7q11.23 dosage and appeared transcriptionally controlled, while translation and ribosomal protein genes followed the opposite trend and were post-transcriptionally buffered. Mechanistically, we uncovered REST regulon as a key mediator of observed phenotypes and rescued transcriptional and excitability alterations through REST inhibition. We identified downregulation of global protein synthesis, mGLUR5 and ERK-mTOR pathways activity in steady-state in both WBS and 7Dup, whereas BDNF stimulation rescued them specifically in 7Dup. Overall, we show that 7q11.23 CNVs alter protein synthesis and neuronal firing-established molecular and cellular phenotypes of neurodevelopmental disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/511483v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1b0fa99org.highwire.dtl.DTLVardef@146624org.highwire.dtl.DTLVardef@13dc89aorg.highwire.dtl.DTLVardef@13d098f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Transient Maternal IL-6 boosts glutamatergic synapses and disrupts hippocampal connectivity in the offspring

Early prenatal inflammatory conditions are thought to represent a risk factor for different neurodevelopmental disorders, with long-term consequences on adult brain connectivity. Here we show that a transient IL-6 elevation, occurring at vulnerable stages of early neurodevelopment, directly impacts brain developmental trajectories through the aberrant enhancement of glutamatergic synapses and overall brain hyper-connectivity. The IL6-mediated boost of excitatory synapse density results from the neuron-autonomous, genomic effect of the transcription factor STAT3 and causally involves the activation of RGS4 gene as a candidate downstream target. The STAT3/RGS4 pathway is also activated in neonatal brains as a consequence of maternal immune activation protocols mimicking a viral infection during pregnancy. By demonstrating that prenatal IL-6 elevations result in aberrant synaptic and brain connectivity through the molecular players identified, we provide a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.

neuroscience↗

bioRxiv2020

Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modelled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

neuroscience↗

bioRxiv2020

Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia

Neuronal circuits assembly requires the fine equilibrium between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized key players in this process, the neuronal molecular components that tag synapses to be eliminated are still undefined. Here we show that exposed phosphatidylserine (PS) represents a neuronal eat-me signal enabling microglial-mediated synapse pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, exposed PS is detectable at both hippocampal and retinogeniculate synapses, where exposure coincides with the onset of synapse elimination and increased PS engulfment by microglia. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, display elevated exposed PS and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated PS exposure that is common among developing brain structures.

neuroscience↗