Biology subjects

Pozzi, D.

Publications and source records attributed to Pozzi, D..

7 recordsLinked to original sources

bioRxiv2026

SUBCELLULAR FUNCTIONS OF UBE3A ISOFORMS DRIVE SYNAPTIC DYSFUNCTION IN ANGELMAN SYNDROME

Genetic defects of the gene encoding the ubiquitin ligase UBE3A cause a severe neurodevelopmental disorder, the Angelman syndrome (AS). The pathophysiology of AS remains unclear, hindering the development of effective therapies. Using AS animal models, we show here that UBE3A controls the development of excitatory and distinct subtypes of inhibitory synapses in cortical pyramidal neurons through cell-autonomous mechanisms, ultimately leading to alteration of synaptic transmission and hyperexcitability. Replacing endogenous Ube3a with individual isoforms, we demonstrate that their uneven nuclear (hUBE3A isoform 1) and cytosolic (hUBE3A isoforms 2/3) distribution is critical for regulating distinct aspects of synaptic development. We also define the molecular requirements underpinning this regulation, showing that: (i) both nuclear and cytosolic UBE3A rely on their ubiquitin ligase activity to ensure proper assembly of synapses; (ii) in addition to the nucleus, UBE3A isoform 1 is also localized in the cytosol, where it is functionally interchangeable with UBE3A isoform 3. Our findings identify a subcellular distribution-dependent mechanism by which UBE3A coordinates cortical circuit development and suggest pathogenic mechanisms of AS.

neuroscience↗

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↗

bioRxiv2023

Mecp2 knock-out astrocytes affect synaptogenesis by IL-6 dependent mechanisms

Synaptic abnormalities represent a hallmark for several neurological diseases and clarification of the underlying mechanisms constitutes a crucial step towards the development of therapeutic strategies. Rett syndrome (RTT) is a rare neurodevelopmental disorder, mainly affecting females, caused by heterozygous mutations in the X-linked Methyl-CpG-Binding Protein 2 (MECP2) gene, leading to a deep derangement of synaptic connectivity. Although initial studies have supported the exclusive involvement of neurons, recent data have highlighted the pivotal contribution of astrocytes in RTT pathogenesis through non-cell autonomous mechanisms. Since astrocytes regulate synaptogenesis by releasing multiple molecules, we investigated the influence of soluble factors secreted by Mecp2 KO astrocytes on synaptic density. We found that Mecp2 deficiency in astrocytes negatively affects their ability to support synapse formation by releasing synaptotoxic molecules, among which we identified interleukin-6 (IL-6). Notably, aberrant IL-6 expression exclusively emerges from a dysfunctional astrocyte-neuron crosstalk, and blocking IL-6 activity prevents synaptic alterations.

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

The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes

Mecp2 deficiency, the gene responsible for Rett syndrome (RTT), affects brain maturation by impairing neuronal activity, transcription and morphology. These three elements are physiologically linked in a feed-forward cycle where neuronal activity modulates transcription and morphology to further increase network maturity. We hypothesized that the reduced activity displayed by maturing Mecp2 null neurons during development could perturb such cycle, sustaining an improper transcriptional program that, ultimately, impairs neuronal maturation. Accordingly, we show that by enhancing activity within an early time window, Ampakine redirects, in vitro, the development of null neuronal networks towards more physiological routes. Similarly, the administration of the drug to newborn null offspring delays the progression of symptoms, significantly prolonging life span. Our data highlights the role of altered neuronal activity during the establishment of Mecp2 null networks and the importance of such early defects to the typically poor maturity of RTT brain functions in adulthood. We propose the existence of an "early molecular phase" of Rett syndrome, a detailed description of which might disclose relevant targets for new rescue treatments.

neuroscience↗