Biology subjects

Pizzirusso, G.

Publications and source records attributed to Pizzirusso, G..

4 recordsLinked to original sources

bioRxiv2025

Reducing methylation of histone 3.3 lysine 4 in the medial ganglionic eminence and hypothalamus recapitulates neurodevelopmental disorder phenotypes

Methylation of lysine 4 on histone H3 (H3K4) is enriched on active promoters and enhancers and correlates with gene activation. Disruption of H3K4 methylation is associated with numerous neurodevelopmental diseases (NDDs) that display intellectual disability and abnormal body growth. Here, we perturb H3K4 methylation in the medial ganglionic eminence (MGE) and the hypothalamus, two brain regions associated with these disease phenotypes. These mutant mice have fewer forebrain interneurons, deficient network rhythmogenesis, and increased spontaneous seizures and seizure susceptibility. Mutant mice are significantly smaller than control littermates, but they eventually became obese due to striking changes in the genetic and cellular hypothalamus environment in these mice. Perturbation of H3K4 methylation in these cells produces deficits in numerous NDD-associated behaviors, with a bias for more severe phenotypes in female mice. Single cell sequencing reveals transcriptional changes in the embryonic and adult brain that underlie many of these phenotypes. In sum, our findings highlight the critical role of H3K4 methylation in regulating survival and cell-specific gene regulatory mechanisms in forebrain GABAergic and hypothalamic cells during neurodevelopment to control network excitability and body size homoeostasis.

neuroscience↗

bioRxiv2025

Alzheimer's Disease Mutations Disrupt Neural Stem Cell Fate and Early Brain Development

Alzheimers disease (AD) has been largely considered as an age-related disease, mainly affecting mature or aging adult brain. Recent studies show that AD-associated mutations could impair early life, even during neurodevelopment. However, due to the complex of AD mutations and neurodevelopmental regulations, how mutations in specific genes affect the origin of neurodevelopment is still largely under studied. In this study, we investigate how AD mutations in App gene impact neurodevelopment, with a focus on NSC dynamics and the balance between neurogenesis and gliogenesis. We employed the 5xFAD transgenic line and the APPNL-G-F knock-in model, RNA sequencing, neurosphere assay and histological analyses on the cortex and hippocampus across critical developmental timepoints. Our results reveal that the APPNL-G-F model exhibits early gene expression changes, with suppressed stem cell proliferation, impaired neurogenesis, upregulation of gliogenesis and enhanced neuroinflammatory pathways. In contrast, the 5xFAD model displays minimal embryonic differences, with pronounced postnatal alterations likely driven by both gene mutations and APP overexpression. These findings indicate that AD mutations can inherently impair NSC self-renewal and differentiation, resulting in a suboptimal brain structure that have potentially higher vulnerability towards AD pathology in later life.

developmental biology↗

bioRxiv2025

Microglia Adopt Temporally Specific Subtypes after Irradiation, Correlating with Neuronal Asynchrony

Cranial radiotherapy causes progressive neurocognitive impairments in cancer survivors. Neuroinflammation is a key contributor, but its dynamics and consequences for brain function remain poorly understood. Here, we performed comprehensive longitudinal profiling from 6 hours to 1 year after irradiation (IR) of the mouse hippocampus, using transcriptomic, protein, and histological analyses. We identified delayed microglial responses initiated by mitotic progression coupled interferon signaling. IR rewired the parenchymal phagocyte profiles, triggered by progressive microglial loss, failure of repopulation through self-renewal, and compensatory generation of microglia-like cells derived from peripheral monocytes. These findings were also observed in autopsied human brain. Finally, we demonstrate two phases of neuronal asynchrony, an early one associated with inflammation and a late one associated with aberrant synaptic regulation. These results provide comprehensive, longitudinal insights into microglia responses that can aid in tailoring therapies to preserve cognition in cancer survivors.

neuroscience↗

bioRxiv2024

Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression.

Alzheimers disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimers disease onset and progression. Characterizing the initial phase of Alzheimers disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used the AppNL-G-F knock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimers disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis-and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory networks functionality. These results suggest that the early loss of microglia could be a pivotal event in the progression of Alzheimers disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.

neuroscience↗