Federico Miozzo

Activity-dependent transcription is a central feature of neuronal plasticity. Here, we show that neuronal activation triggers genome-wide redistribution of CBP and p300 in hippocampal neurons. Upon stimulation, KAT3 cofactors relocate from super-enhancers supporting neuronal identity to enhancers associated with activity-regulated genes, accompanied by transient changes in H3K27ac, chromatin accessibility, and three-dimensional genome architecture. Mechanistically, distinct TF families control KAT3 shuttling: proneural bHLH factors such as NeuroD2 maintain cofactor occupancy at identity-associated regulatory elements, whereas AP-1 binds de novo at plasticity-associated loci. This dynamic redistribution reshapes enhancer landscapes and chromatin interactions, enabling robust activation of plasticity genes while transiently attenuating neuronal identity programs. Remarkably, FOS overexpression is sufficient to reproduce the repression of neuronal identity genes observed during stimulation. Together, our findings reveal a reversible competition between transcriptional networks governing neuronal identity and plasticity and identify KAT3 redistribution as a key mechanism coupling neuronal activity to large-scale chromatin remodeling.

Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental conditions characterized by deficits in social communication and repetitive behaviours, collectively affecting nearly 2% of the global population. ASD is strongly heritable, with genetic variants converging on molecular pathways that regulate synaptic connectivity. Protocadherins, particularly nonclustered protocadherins (ncPCDHs), have emerged as high-confidence ASD-associated genes. By mediating cell surface adhesion and downstream signalling, ncPCDHs regulate essential neurodevelopmental processes ranging from neuronal production and migration to synaptic maturation, while generating combinatorial surface codes that organize circuit wiring—all mechanisms highly relevant to ASD. Here, we review recent findings from human genetics and rodent models, highlighting activity-dependent signalling as a central hub through which ncPCDHs coordinate synaptic refinement and maintain excitatory/inhibitory balance. Finally, we discuss how dissecting ncPCDH molecular mechanisms may clarify ASD pathogenesis and inform targeted therapeutic strategies.

RATIONALE: Environmental enrichment (EE) paradigms in rodents have long demonstrated that enhanced sensory, cognitive, social, and motor stimulation positively impacts brain function, improving learning, memory, and neuroplasticity. These effects have significant implications for understanding cognitive development and mitigating cognitive decline and brain aging. While numerous transcriptomic studies have explored EE-induced molecular changes, a unified view of the genes and pathways consistently modulated remains lacking. METHODS: To address this gap, we performed a systematic review and meta-analysis. We conducted a comprehensive PubMed search for all studies published up to February 2025 that matched all the following inclusion criteria: (1) employed EE paradigms; (2) were conducted on rodents; (3) utilized genome-wide transcriptomic methods; (4) examined brain regions or neuronal populations. The 323 retrieved articles were manually screened for relevance to the study aims and data availability. Datasets from 20 eligible RNA-seq reports were reprocessed using a unified analysis pipeline and subjected to a meta-analysis with three complementary statistical methods. RESULTS: Despite considerable heterogeneity across studies, our integrative analysis identified consistent gene expression signatures linked to synaptic function, plasticity and their transcriptional regulation. These molecular insights advance our understanding of how EE impacts on neuronal and behavioural outcomes, and may inform therapeutic strategies aimed at replicating or enhancing EE benefits. To promote open science and foster further research, we developed an accessible web application, mEEtaBrain, that enables the neuroscience community to navigate and interrogate our meta-analysis results.

Protocadherins are key regulators of neurodevelopment and synaptic function, acting not only as adhesion molecules but also as synaptic hubs for intracellular signaling. Here, we uncover a novel activity-dependent signaling pathway for Pcdh9 , a protocadherin linked to Autism Spectrum Disorder and Major Depressive Disorder. By combining biochemical and immunohistochemistry approaches on neuronal cultures, we show that neuronal activity triggers Matrix Metalloproteases (MMP)-dependent cleavage of PCDH9, generating a C-terminal fragment (CTF) that translocates to the nucleus. PCDH9 CTF overexpression promotes dendritic growth, increases spine density, and concomitantly strengthens excitatory synaptic transmission. These findings identify PCDH9 CTF as a novel activity-dependent signaling molecule that links synaptic activity to structural remodeling and functional modulation, suggesting a new mechanism by which synaptic activity shapes neuronal properties.

Environmental enrichment (EE) paradigms in rodents have long demonstrated that enhanced sensory, cognitive, social, and motor stimulation positively impacts brain function, improving learning, memory, and neuroplasticity. These effects have significant implications for understanding cognitive development and mitigating cognitive decline and brain aging. While numerous transcriptomic studies have explored EE-induced molecular changes, a unified view of the genes and pathways consistently modulated remains lacking. To address this gap, we performed a systematic review and meta-analysis. We conducted a comprehensive PubMed search for all studies published up to February 2025 that matched all the following inclusion criteria: (1) employed EE paradigms; (2) were conducted on rodents; (3) utilized genome-wide transcriptomic methods; (4) examined brain regions or neuronal populations. The 323 retrieved articles were manually screened for relevance to the study aims and data availability. Datasets from 20 eligible RNA-seq reports were reprocessed using a unified analysis pipeline and subjected to a meta-analysis with three complementary statistical methods. Despite considerable heterogeneity across studies, our integrative analysis identified consistent gene expression signatures linked to synaptic function, plasticity and their transcriptional regulation. In particular, our findings highlight the upregulation of the activity-dependent transcriptional program, including Fos and Jun family members. These molecular insights advance our understanding of how EE impacts on neuronal and behavioral outcomes, and may inform therapeutic strategies aimed at replicating or enhancing EE benefits. To promote open science and foster further research, we developed an accessible web application, mEEtaBrain, that enables the neuroscience community to navigate and interrogate our meta-analysis results. Substantial methodological heterogeneity across source studies increased variability in the meta-analysis outcomes. The use of stressors or disease models, particularly in rat studies, introduced a major confounding factor and limited reliable interspecies comparison. Overall, the studies exhibited a low to moderate risk of bias.

Environmental conditions profoundly influence cognitive development, particularly during early life. Transcriptional and epigenetic mechanisms may serve as molecular substrates for the lasting effects of environmental enrichment (EE) and impoverishment (IE) on cognitive abilities and hippocampal function. However, the specific gene programs driving these changes remain largely unknown. In this study using female mice, EE and IE produced opposite effects on cognitive performance. By combining hippocampal microdissection and genetic tagging of neuronal nuclei with genome-wide analyses of gene expression, chromatin accessibility, histone acetylation, and DNA methylation, we uncovered profound differences in the transcriptional and epigenetic profiles of CA1 pyramidal neurons and dentate gyrus (DG) granule neurons. These analyses revealed cell type-specific genomic changes induced by EE and IE, highlighting distinct patterns of neuroadaptation within each population. This multiomic screen pinpointed the activity-regulated transcription factor AP-1 as a crucial mediator of neuroadaptation to conditions during early life in both cell types, albeit through distinct downstream mechanisms. Conditional deletion of Fos, a core AP-1 subunit, in excitatory neurons hampered EE-induced cognitive enhancement, further underscoring the pivotal role of this transcription factor in neuroadaptation.

While aging impairs memory precision, its effects on engram dynamics and gene expression remain poorly understood. To address this, we used TRAP2 activity-reporter mice, nuclear tagging, and FOS-based activity mapping to track neurons activated during contextual fear memory encoding and reactivated during recall in young and aged mice. Across 378 brain regions, we quantified engram size, spatial distribution, and reactivation stability. We further applied fluorescence-activated nuclear sorting (FANS) combined with single-nucleus RNA sequencing (snRNA-seq) to characterize gene expression changes associated with memory encoding and recall across diverse cell types. In addition, we compared the transcriptional profiles of first-time versus second-time neuronal responder cells in the dentate gyrus. Aged brains exhibited altered engram allocation, reduced reactivation stability, and distinct gene expression patterns during memory retrieval. These findings reveal age-related changes in the organization and molecular identity of memory traces, providing mechanistic insight into cognitive decline and highlighting potential targets for intervention.

Environmental conditions profoundly influence cognitive development, particularly during early life. Transcriptional and epigenetic mechanisms may serve as molecular substrates for the lasting effects of environmental enrichment (EE) and impoverishment (IE) on cognitive abilities and hippocampal function. However, the specific gene programs driving these changes remain largely unknown. In this study, EE and IE modulated the cognitive abilities of mice in opposing directions. By combining hippocampal microdissection and genetic tagging of neuronal nuclei with genome-wide analyses of gene expression, chromatin accessibility, histone acetylation, and DNA methylation, we uncovered profound differences in the transcriptional and epigenetic profiles of CA1 pyramidal neurons and dentate gyrus (DG) granule neurons. These analyses revealed cell type-specific genomic changes induced by EE and IE, highlighting distinct patterns of neuroadaptation within each population. This multiomic screen pinpointed the activity-regulated transcription factor AP-1 as a crucial mediator of neuroadaptation to conditions during early life in both cell types, albeit through distinct downstream mechanisms. Conditional deletion of Fos , a core AP-1 subunit, in excitatory neurons hampered EE-induced cognitive enhancement, further underscoring the pivotal role of this transcription factor in neuroadaptation.

Protocadherins, a family of adhesion molecules with a crucial role in cell–cell interactions, have emerged as key players in neurodevelopmental and psychiatric disorders. In particular, growing evidence links genetic alterations in the protocadherin 9 ( PCDH9 ) gene with autism spectrum disorder and major depressive disorder. Furthermore, Pcdh9 deletion induces neuronal defects in the mouse somatosensory cortex, accompanied by sensorimotor and memory impairment. However, the synaptic and molecular mechanisms of PCDH9 in the brain remain largely unknown, particularly concerning its impact on brain pathology. To address this question, we conducted a comprehensive investigation of PCDH9’s role in the male mouse hippocampus at the ultrastructural, biochemical, transcriptomic, electrophysiological, and network levels. We show that PCDH9 mainly localizes at glutamatergic synapses and its expression peaks in the first week after birth, a crucial time window for synaptogenesis. Strikingly, Pcdh9 KO neurons exhibit oversized presynaptic terminal and postsynaptic density in the CA1. Synapse overgrowth is sustained by the widespread upregulation of synaptic genes, as revealed by single-nucleus RNA-seq (snRNA-seq), and the dysregulation of key drivers of synapse morphogenesis, including the SHANK2/CORTACTIN pathway. At the functional level, these structural and transcriptional abnormalities result in increased excitatory postsynaptic currents (mEPSC) and reduced network activity in the CA1 of Pcdh9 KO mice. In conclusion, our work uncovers Pcdh9 ’s pivotal role in shaping the morphology and function of CA1 excitatory synapses, thereby modulating glutamatergic transmission within hippocampal circuits.