Biology subjects

De Rocco, G.

Publications and source records attributed to De Rocco, G..

3 recordsLinked to original sources

bioRxiv2026

Early AMPA receptor potentiation modifies synaptic maturation and disease progression in Rett models

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in MECP2 and characterized by impaired neuronal maturation and synaptic dysfunction. Positive allosteric modulators of AMPA receptors (AMPAR-PAMs) have shown therapeutic promise in RTT models, but the determinants of treatment responsiveness remain unclear. Here, we evaluated the clinically advanced AMPAR-PAM CX1632 in Mecp2-null male and Mecp2-heterozygous female mice across developmental stages and treatment regimens. Therapeutic efficacy was strongly influenced by developmental stage, disease severity, and treatment schedule. Brief neonatal treatment produced long-lasting improvements in survival, disease progression, motor function, and cognition, whereas later intervention was markedly less effective in symptomatic null mice but remained beneficial in less severely affected heterozygous females. Repeated intermittent administration further enhanced selected benefits. Mechanistically, early CX1632 treatment induced sustained activation of neuronal and synaptic gene programs, restored synaptic organization and neuronal activity, and rescued AMPA receptor-mediated transmission weeks after drug withdrawal. These findings identify disease stage as a key determinant of responsiveness to AMPA receptor potentiation and support developmentally informed therapeutic strategies for MECP2-related disorders.

neuroscience↗

bioRxiv2025

Spatially resolved mapping of histones reveal selective neuronal response in Rett syndrome

Rett Syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in the X-linked MECP2 gene, results in profound life-long neurological dysfunction. RTT patients live an apparently normal initial life until 12-18 months of age following which, a progressive accumulation of a wide range of phenotypic manifestations sets in. While MeCP2 is known to regulate chromatin, its impact on global histone composition and dynamics remains poorly understood. Here, we combine mass spectrometry imaging (MSI) and laser capture microdissection (LCM) coupled to LC-MS/MS to systematically profile histone proteoforms in three key brain regions: the dentate gyrus (DG) and cornu ammonis (CA) of the hippocampus, and the cerebellum (Cb). Our analysis reveals striking neuron-specific differences in histone composition between Mecp2-deficient and wildtype (WT) mice. Interestingly, the expression of a pathogenic Mecp2 missense mutant (Y120D) results in subtler changes in histone composition that are distinct from the null mutations. This study provides the first spatially resolved epigenetic atlas of histone proteoforms in RTT and suggests that Mecp2 loss perturbs chromatin homeostasis in a neuron- and mutation-dependent manner. Our findings underscore the critical need for cell-type-resolved analyses to unravel the mechanistic underpinnings of RTT and emphasize the importance of personalised therapeutic strategies that consider both the affected cell-type and particular Mecp2 mutation.

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↗