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152 results on '"Mazziotti, Raffaele"'

1. Brain histone beta-hydroxybutyrylation couples metabolism with gene expression

Author

Cornuti, Sara, Chen, Siwei, Lupori, Leonardo, Finamore, Francesco, Carli, Fabrizia, Samad, Muntaha, Fenizia, Simona, Caldarelli, Matteo, Damiani, Francesca, Raimondi, Francesco, Mazziotti, Raffaele, Magnan, Christophe, Rocchiccioli, Silvia, Gastaldelli, Amalia, Baldi, Pierre, and Tognini, Paola

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Brain Disorders, Human Genome, Neurosciences, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Mice, Animals, Histones, 3-Hydroxybutyric Acid, Ketone Bodies, Brain, Gene Expression, Fasting, Cerebral cortex, Beta-hydroxybutyrylation, Transcriptome, Epigenome, Physiology, Clinical Sciences, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Oncology and carcinogenesis
Abstract

Little is known about the impact of metabolic stimuli on brain tissue at a molecular level. The ketone body beta-hydroxybutyrate (BHB) can be a signaling molecule regulating gene transcription. Thus, we assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex of mice undergoing a ketogenic metabolic challenge (48 h fasting). We found that fasting enhanced K-bhb in a variety of proteins including histone H3. ChIP-seq experiments showed that K9 beta-hydroxybutyrylation of H3 (H3K9-bhb) was significantly enriched by fasting on more than 8000 DNA loci. Transcriptomic analysis showed that H3K9-bhb on enhancers and promoters correlated with active gene expression. One of the most enriched functional annotations both at the epigenetic and transcriptional level was "circadian rhythms''. Indeed, we found that the diurnal oscillation of specific transcripts was modulated by fasting at distinct zeitgeber times both in the cortex and suprachiasmatic nucleus. Moreover, specific changes in locomotor activity daily features were observed during re-feeding after 48-h fasting. Thus, our results suggest that fasting remarkably impinges on the cerebral cortex transcriptional and epigenetic landscape, and BHB acts as a powerful epigenetic molecule in the brain through direct and specific histone marks remodeling in neural tissue cells.

Published
2023

2. Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency

Author

Ghirardini, Elsa, Sagona, Giulia, Marquez-Galera, Angel, Calugi, Francesco, Navarron, Carmen M, Cacciante, Francesco, Chen, Siwei, Di Vetta, Federica, Dadà, Lorenzo, Mazziotti, Raffaele, Lupori, Leonardo, Putignano, Elena, Baldi, Pierre, Lopez-Atalaya, Jose P, Pizzorusso, Tommaso, and Baroncelli, Laura

Subjects
Biomedical and Clinical Sciences, Neurosciences, Genetics, Brain Disorders, Neurodegenerative, Epilepsy, Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Mice, Brain Diseases, Metabolic, Inborn, Creatine, Neurons, Parvalbumins, Membrane Transport Proteins, Creatine transporter deficiency, Neurodevelopmental disorders, Parvalbumin neurons, Energy metabolism, Synapse, Biochemistry and Cell Biology, Clinical Sciences, Biochemistry and cell biology
Abstract

Mutations in the solute carrier family 6-member 8 (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering the development of therapies. In this study, we generated an extensive transcriptomic profile of CTD showing that Cr deficiency causes perturbations of gene expression in excitatory neurons, inhibitory cells, and oligodendrocytes which result in remodeling of circuit excitability and synaptic wiring. We also identified specific alterations of parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional electrophysiological phenotype. Mice lacking Slc6a8 only in PV+ interneurons recapitulated numerous CTD features, including cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ interneurons is sufficient to determine the neurological phenotype of CTD. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses significantly improved cortical activity in Slc6a8 knock-out animals. Altogether, these data demonstrate that Slc6a8 is critical for the normal function of PV+ interneurons and that impairment of these cells is central in the disease pathogenesis, suggesting a novel therapeutic venue for CTD.

Published
2023

5. Assessing Pattern Recognition Performance of Neuronal Cultures through Accurate Simulation

Author

Lagani, Gabriele, Mazziotti, Raffaele, Falchi, Fabrizio, Gennaro, Claudio, Cicchini, Guido Marco, Pizzorusso, Tommaso, Cremisi, Federico, and Amato, Giuseppe

Subjects
Computer Science - Computer Vision and Pattern Recognition
Abstract

Previous work has shown that it is possible to train neuronal cultures on Multi-Electrode Arrays (MEAs), to recognize very simple patterns. However, this work was mainly focused to demonstrate that it is possible to induce plasticity in cultures, rather than performing a rigorous assessment of their pattern recognition performance. In this paper, we address this gap by developing a methodology that allows us to assess the performance of neuronal cultures on a learning task. Specifically, we propose a digital model of the real cultured neuronal networks; we identify biologically plausible simulation parameters that allow us to reliably reproduce the behavior of real cultures; we use the simulated culture to perform handwritten digit recognition and rigorously evaluate its performance; we also show that it is possible to find improved simulation parameters for the specific task, which can guide the creation of real cultures., Comment: 4 pages, 2 figures. Submitted to NER 2021 conference

Published
2020

6. MiR‐29 coordinates age‐dependent plasticity brakes in the adult visual cortex

Author

Napoli, Debora, Lupori, Leonardo, Mazziotti, Raffaele, Sagona, Giulia, Bagnoli, Sara, Samad, Muntaha, Sacramento, Erika Kelmer, Kirkpartick, Joanna, Putignano, Elena, Chen, Siwei, Tozzini, Eva Terzibasi, Tognini, Paola, Baldi, Pierre, Kwok, Jessica CF, Cellerino, Alessandro, and Pizzorusso, Tommaso

Subjects
Eye Disease and Disorders of Vision, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Animals, Dominance, Ocular, Mice, Mice, Inbred C57BL, MicroRNAs, Neuronal Plasticity, Proteomics, Visual Cortex, DNA methylation, microRNA, ocular dominance plasticity, perineuronal net, Biochemistry and Cell Biology, Developmental Biology
Abstract

Visual cortical circuits show profound plasticity during early life and are later stabilized by molecular "brakes" limiting excessive rewiring beyond a critical period. The mechanisms coordinating the expression of these factors during the transition from development to adulthood remain unknown. We found that miR-29a expression in the visual cortex dramatically increases with age, but it is not experience-dependent. Precocious high levels of miR-29a blocked ocular dominance plasticity and caused an early appearance of perineuronal nets. Conversely, inhibition of miR-29a in adult mice using LNA antagomirs activated ocular dominance plasticity, reduced perineuronal nets, and restored their juvenile chemical composition. Activated adult plasticity had the typical functional and proteomic signature of critical period plasticity. Transcriptomic and proteomic studies indicated that miR-29a manipulation regulates the expression of plasticity brakes in specific cortical circuits. These data indicate that miR-29a is a regulator of the plasticity brakes promoting age-dependent stabilization of visual cortical connections.

Published
2020

9. Mir-132/212 is required for maturation of binocular matching of orientation preference and depth perception

Author

Mazziotti, Raffaele, Baroncelli, Laura, Ceglia, Nicholas, Chelini, Gabriele, Sala, Grazia Della, Magnan, Christophe, Napoli, Debora, Putignano, Elena, Silingardi, Davide, Tola, Jonida, Tognini, Paola, Arthur, J Simon C, Baldi, Pierre, and Pizzorusso, Tommaso

Subjects
Biomedical and Clinical Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Genetics, Neurosciences, Biotechnology, Eye Disease and Disorders of Vision, Aetiology, 2.1 Biological and endogenous factors, Animals, Depth Perception, Electrophysiology, Female, Gene Deletion, Genotype, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, Neuronal Plasticity, Neurons, Orientation, Sequence Analysis, RNA, Transcriptome, Up-Regulation, Vision, Binocular, Visual Cortex, Visual Perception
Abstract

MicroRNAs (miRNAs) are known to mediate post-transcriptional gene regulation, but their role in postnatal brain development is still poorly explored. We show that the expression of many miRNAs is dramatically regulated during functional maturation of the mouse visual cortex with miR-132/212 family being one of the top upregulated miRNAs. Age-downregulated transcripts are significantly enriched in miR-132/miR-212 putative targets and in genes upregulated in miR-132/212 null mice. At a functional level, miR-132/212 deletion affects development of receptive fields of cortical neurons determining a specific impairment of binocular matching of orientation preference, but leaving orientation and direction selectivity unaltered. This deficit is associated with reduced depth perception in the visual cliff test. Deletion of miR-132/212 from forebrain excitatory neurons replicates the binocular matching deficits. Thus, miR-132/212 family shapes the age-dependent transcriptome of the visual cortex during a specific developmental window resulting in maturation of binocular cortical cells and depth perception.

Published
2017

10. From pupil to the brain: New insights for studying cortical plasticity through pupillometry

Author

Viglione, Aurelia, Mazziotti, Raffaele, Pizzorusso, Tommaso, Viglione, Aurelia, Mazziotti, Raffaele, and Pizzorusso, Tommaso

Subjects
Cellular and Molecular Neuroscience, Pupillometry, pupil size, Cognitive Neuroscience, neuromodulation, noradrenaline, Neuroscience (miscellaneous), cortical plasticity, locus coeruleu, Settore BIO/09 - Fisiologia, Sensory Systems, norepinephrine
Abstract

Pupil size variations have been associated with changes in brain activity patterns related with specific cognitive factors, such as arousal, attention, and mental effort. The locus coeruleus (LC), a key hub in the noradrenergic system of the brain, is considered to be a key regulator of cognitive control on pupil size, with changes in pupil diameter corresponding to the release of norepinephrine (NE). Advances in eye-tracking technology and open-source software have facilitated accurate pupil size measurement in various experimental settings, leading to increased interest in using pupillometry to track the nervous system activation state and as a potential biomarker for brain disorders. This review explores pupillometry as a non-invasive and fully translational tool for studying cortical plasticity starting from recent literature suggesting that pupillometry could be a promising technique for estimating the degree of residual plasticity in human subjects. Given that NE is known to be a critical mediator of cortical plasticity and arousal, the review includes data revealing the importance of the LC-NE system in modulating brain plasticity and pupil size. Finally, we will review data suggesting that pupillometry could provide a quantitative and complementary measure of cortical plasticity also in pre-clinical studies.

Published
2023

14. Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency

Author

Ministero della Salute, Cassa di Risparmio di Firenze, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), CSIC-UMH - Instituto de Neurociencias (IN), Ghirardini, Elsa, Sagona, Giulia, Marquez-Galera, Angel, Calugi, Francesco, Navarrón, Carmen M., Cacciante, Francesco, Chen, Siwei, Di Vetta, Federica, Dadà, Lorenzo, Mazziotti, Raffaele, Lupori, Leonardo, Putignano, Elena, Baldi, Pierre, López-Atalaya, José P., Pizzorusso, Tommaso, Baroncelli, Laura, Ministero della Salute, Cassa di Risparmio di Firenze, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), CSIC-UMH - Instituto de Neurociencias (IN), Ghirardini, Elsa, Sagona, Giulia, Marquez-Galera, Angel, Calugi, Francesco, Navarrón, Carmen M., Cacciante, Francesco, Chen, Siwei, Di Vetta, Federica, Dadà, Lorenzo, Mazziotti, Raffaele, Lupori, Leonardo, Putignano, Elena, Baldi, Pierre, López-Atalaya, José P., Pizzorusso, Tommaso, and Baroncelli, Laura

Abstract

Mutations in the solute carrier family 6-member 8 (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering the development of therapies. In this study, we generated an extensive transcriptomic profile of CTD showing that Cr deficiency causes perturbations of gene expression in excitatory neurons, inhibitory cells, and oligodendrocytes which result in remodeling of circuit excitability and synaptic wiring. We also identified specific alterations of parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional electrophysiological phenotype. Mice lacking Slc6a8 only in PV+ interneurons recapitulated numerous CTD features, including cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ interneurons is sufficient to determine the neurological phenotype of CTD. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses significantly improved cortical activity in Slc6a8 knock-out animals. Altogether, these data demonstrate that Slc6a8 is critical for the normal function of PV+ interneurons and that impairment of these cells is central in the disease pathogenesis, suggesting a novel therapeutic venue for CTD.

Published
2023

15. Supplementary Information: Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency

Author

Ghirardini, Elsa, Sagona, Giulia, Marquez-Galera, Angel, Calugi, Francesco, Navarrón, Carmen M., Cacciante, Francesco, Chen, Siwei, Di Vetta, Federica, Dadà, Lorenzo, Mazziotti, Raffaele, Lupori, Leonardo, Putignano, Elena, Baldi, Pierre, López-Atalaya, José P., Pizzorusso, Tommaso, Baroncelli, Laura, Ghirardini, Elsa, Sagona, Giulia, Marquez-Galera, Angel, Calugi, Francesco, Navarrón, Carmen M., Cacciante, Francesco, Chen, Siwei, Di Vetta, Federica, Dadà, Lorenzo, Mazziotti, Raffaele, Lupori, Leonardo, Putignano, Elena, Baldi, Pierre, López-Atalaya, José P., Pizzorusso, Tommaso, and Baroncelli, Laura

Abstract

Additional file 1: Supplementary Materials and Methods and Supplementary figures S1, S2, S3, S4, S5, S6, S7, S8. Additional file 2: Table S1. List of differentially expressed genes in bulk RNA-seq. Additional file 3: Table S2. Quantitative PCR validation of top differentially-expressed genes. Additional file 4: Table S3. Gene Ontology analysis for biological process for up- and downregulated genes in bulk RNA-seq. Additional file 5: Table S4. Gene Ontology analysis for cellular component for up- and downregulated genes in bulk RNA-seq. Additional file 6: Table S5. Clusters of protein-protein interactions (PPI) for the corresponding proteins of up- and downregulated genes in bulk RNA-seq. Additional file 7: Table S6. List of population marker genes used for supervised clustering analysis of snRNA-seq data. Additional file 8: Table S7. Quantification of cells belonging to each of the major population clusters in snRNA-seq data. Additional file 9: Table S8. List of differentially expressed genes in major sn-RNAseq clusters. Additional file 10: Table S9. Gene Ontology analysis for biological process for up- and downregulated genes in major sn-RNAseq clusters. Additional file 11: Table S10. Gene Ontology analysis for cellular component for up- and downregulated genes in major sn-RNAseq clusters. Additional file 12: Table S11. Number of reads for each biological replicate in bulk RNA-seq. Additional file 13: Table S12. Primer sequences for qPCR.

Published
2023

16. Predicting Visual Stimuli From Cortical Response Recorded With Wide-Field Imaging in a Mouse

Author

De Luca, Daniela, Moccia, Sara, Lupori, Leonardo, Mazziotti, Raffaele, Pizzorusso, T., and Micera, Silvestro

Abstract

Neural decoding of the visual system is a subject of research interest, both to understand how the visual system works and to be able to use this knowledge in areas, such as computer vision or brain–computer interfaces. Spike-based decoding is often used, but it is difficult to record data from the whole visual cortex, and it requires proper preprocessing. We here propose a decoding method that combines wide-field calcium brain imaging, which allows us to obtain large-scale visualization of cortical activity with a high signal-to-noise ratio (SNR), and convolutional neural networks (CNNs). A mouse was presented with ten different visual stimuli, and the activity from its primary visual cortex (V1) was recorded. A CNN we designed was then compared with other existing commonly used CNNs, that were trained to classify the visual stimuli from wide-field calcium imaging images, obtaining a weighted $F1$ score of more than 0.70 on the test set, showing it is possible to automatically detect what is present in the visual field of the animal.

Published
2024
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17. A Comprehensive Atlas of Perineuronal Net Distribution and Colocalization with Parvalbumin in the Adult Mouse Brain

Author

Lupori, Leonardo, primary, Totaro, Valentino, additional, Cornuti, Sara, additional, Ciampi, Luca, additional, Carrara, Fabio, additional, Grilli, Edda, additional, Viglione, Aurelia, additional, Tozzi, Francesca, additional, Putignano, Elena, additional, Mazziotti, Raffaele, additional, Amato, Giuseppe, additional, Gennaro, Claudio, additional, Tognini, Paola, additional, and Pizzorusso, Tommaso, additional

Published
2023
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18. Predicting visual stimuli from cortical response recorded with widefield imaging in a mouse

Author

De Luca, Daniela, Moccia, Sara, Lupori, Leonardo, Mazziotti, Raffaele, Pizzorusso, Tommaso, and Micera, Silvestro

Subjects
deep learning, visual cortex, wide-field imaging, visual prostheses
Abstract

Optic nerve stimulation holds great potential for visual prostheses. Its effectiveness depends on the stimulation protocol, which can be optimized to achieve cortical activation similar to that evoked in response to visual stimuli. To identify a target cortical activation, it is necessary to characterize the cortical response. We here propose a convolutional neural network (CNN) to do it exploiting widefield calcium brain images, which allow large-scale visualization of cortical activity with high signal-to-noise ratio. A mouse was presented with 10 different visual stimuli, and the activity from its primary visual cortex (V1) was recorded. The CNN was trained to predict the visual stimulus, with an accuracy of 78.46%+/- 3.31% on the test set, showing it is possible to automatically detect what is present in the visual field of the animal.

Published
2022

20. mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder

Author

Gurgone, Antonia, primary, Pizzo, Riccardo, additional, Raspanti, Alessandra, additional, Chiantia, Giuseppe, additional, Devi, Sunaina, additional, Comai, Debora, additional, Morello, Noemi, additional, Pilotto, Federica, additional, Gnavi, Sara, additional, Lupori, Leonardo, additional, Mazziotti, Raffaele, additional, Sagona, Giulia, additional, Putignano, Elena, additional, Nocentini, Alessio, additional, Supuran, Claudiu T., additional, Marcantoni, Andrea, additional, Pizzorusso, Tommaso, additional, and Giustetto, Maurizio, additional

Published
2022
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22. A Potential Biomarker of Brain Activity in Autism Spectrum Disorders: A Pilot fNIRS Study in Female Preschoolers.

Author

Scaffei, Elena, Mazziotti, Raffaele, Conti, Eugenia, Costanzo, Valeria, Calderoni, Sara, Stoccoro, Andrea, Carmassi, Claudia, Tancredi, Raffaella, Baroncelli, Laura, and Battini, Roberta

Subjects
*AUTISM spectrum disorders, *PRESCHOOL children, *NEAR infrared spectroscopy, *BIOMARKERS, *PILOT projects
Abstract

Autism spectrum disorder (ASD) refers to a neurodevelopmental condition whose detection still remains challenging in young females due to the heterogeneity of the behavioral phenotype and the capacity of camouflage. The availability of quantitative biomarkers to assess brain function may support in the assessment of ASD. Functional Near-infrared Spectroscopy (fNIRS) is a non-invasive and flexible tool that quantifies cortical hemodynamic responses (HDR) that can be easily employed to describe brain activity. Since the study of the visual phenotype is a paradigmatic model to evaluate cerebral processing in many neurodevelopmental conditions, we hypothesized that visually-evoked HDR (vHDR) might represent a potential biomarker in ASD females. We performed a case-control study comparing vHDR in a cohort of high-functioning preschooler females with ASD (fASD) and sex/age matched peers. We demonstrated the feasibility of visual fNIRS measurements in fASD, and the possibility to discriminate between fASD and typical subjects using different signal features, such as the amplitude and lateralization of vHDR. Moreover, the level of response lateralization was correlated to the severity of autistic traits. These results corroborate the cruciality of sensory symptoms in ASD, paving the way for the validation of the fNIRS analytical tool for diagnosis and treatment outcome monitoring in the ASD population. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Looking for “fNIRS Signature” in Autism Spectrum: A Systematic Review Starting From Preschoolers

Author

Conti, Eugenia, primary, Scaffei, Elena, additional, Bosetti, Chiara, additional, Marchi, Viviana, additional, Costanzo, Valeria, additional, Dell’Oste, Valerio, additional, Mazziotti, Raffaele, additional, Dell’Osso, Liliana, additional, Carmassi, Claudia, additional, Muratori, Filippo, additional, Baroncelli, Laura, additional, Calderoni, Sara, additional, and Battini, Roberta, additional

Published
2022
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29. MEYE: Web App for Translational and Real-Time Pupillometry

Author

Mazziotti, Raffaele, primary, Carrara, Fabio, additional, Viglione, Aurelia, additional, Lupori, Leonardo, additional, Lo Verde, Luca, additional, Benedetto, Alessandro, additional, Ricci, Giulia, additional, Sagona, Giulia, additional, Amato, Giuseppe, additional, and Pizzorusso, Tommaso, additional

Published
2021
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34. Brain histone beta-hydroxy-butyrylation couples metabolism with gene expression

Author

Cornuti, Sara, primary, Lupori, Leonardo, additional, Chen, Siwei, additional, Finamore, Francesco, additional, Samad, Muntaha, additional, Raimondi, Francesco, additional, Mazziotti, Raffaele, additional, Magnan, Christophe, additional, Rocchiccioli, Silvia, additional, Baldi, Pierre, additional, Pizzorusso, Tommaso, additional, and Tognini, Paola, additional

Published
2021
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40. Novel translational phenotypes and biomarkers for creatine transporter deficiency

Author

Mazziotti, Raffaele, primary, Cacciante, Francesco, additional, Sagona, Giulia, additional, Lupori, Leonardo, additional, Gennaro, Mariangela, additional, Putignano, Elena, additional, Alessandrì, Maria Grazia, additional, Ferrari, Annarita, additional, Battini, Roberta, additional, Cioni, Giovanni, additional, Pizzorusso, Tommaso, additional, and Baroncelli, Laura, additional

Published
2020
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42. FRI-067-Management of primary biliary cholangitis in the pre-obeticholic acid era, and the rate of non-response to ursodeoxycholic acid (UDCA), in a large real-world cohort of PBC patients in Italy: The CLEO-AIGO database

Author

Gentilucci, Umberto Vespasiani, primary, Rosina, Floriano, additional, Chessa, Luchino, additional, Palitti, Valeria Pace, additional, Picardi, Antonio, additional, Barlattani, Michela, additional, Barlattani, Angelo, additional, Feletti, Valentina, additional, Musetto, Alessandro, additional, Zolfino, Teresa, additional, russello, maurizio, additional, Cannavo, Maria rita, additional, Cozzolongo, Raffaele, additional, Losito, Francesco, additional, Garrucciu, Giovanni, additional, Niro, Grazia, additional, Fontana, Rosanna, additional, Bacca, Donato, additional, Cardinale, Giada, additional, Grasso, Alessandro, additional, Storato, Silvia, additional, Bertino, Gaetano, additional, Frazzetto, Evelise, additional, Scifo, Gaetano, additional, D’adamo, Giuseppe, additional, Fimiani, Basilio, additional, Sacco, Rodolfo, additional, Ricchiuti, Angelo, additional, Ascione, Antonio, additional, Paolo, Tundo, additional, Distefano, Marco, additional, Tarquini, Pierluigi, additional, Marrone, Aldo, additional, Bardon, Valeria, additional, Candilo, Francesco Di, additional, Francavilla, Ruggiero, additional, Madonia, Salvatore, additional, Claar, Ernesto, additional, Adinolfi, Luigi Elio, additional, Puoti, Claudio, additional, Mazziotti, Raffaele, additional, Ubalducci, Giuseppina, additional, D’antò, Maria, additional, Clementi, Carlo, additional, Pellicelli, Adriano, additional, and Izzi, Antonio, additional

Published
2019
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43. p75 Neurotrophin Receptor Activation Regulates the Timing of the Maturation of Cortical Parvalbumin Interneuron Connectivity and Promotes Juvenile-like Plasticity in Adult Visual Cortex

Author

Baho, Elie, primary, Chattopadhyaya, Bidisha, additional, Lavertu-Jolin, Marisol, additional, Mazziotti, Raffaele, additional, Awad, Patricia N., additional, Chehrazi, Pegah, additional, Groleau, Marianne, additional, Jahannault-Talignani, Celine, additional, Vaucher, Elvire, additional, Ango, Fabrice, additional, Pizzorusso, Tommaso, additional, Baroncelli, Laura, additional, and Di Cristo, Graziella, additional

Published
2019
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44. p75 Neurotrophin Receptor Regulates the Timing of the Maturation of Cortical Parvalbumin Cell Connectivity and Promotes Ocular Dominance Plasticity in Adult Visual Cortex

Author

Baho, Elie, primary, Chattopadhyaya, Bidisha, additional, Lavertu-Jolin, Marisol, additional, Mazziotti, Raffaele, additional, Awad, Patricia N, additional, Chehrazi, Pegah, additional, Groleau, Marianne, additional, Jahannault-Talignani, Celine, additional, Sanon, Nathalie T., additional, Vaucher, Elvire, additional, Ango, Fabrice, additional, Pizzorusso, Tommaso, additional, Baroncelli, Laura, additional, and Cristo, Graziella Di, additional

Published
2018
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45. CDKL5 protein substitution therapy rescues neurological phenotypes of a mouse model of CDKL5 disorder

Author

Trazzi, Stefania, primary, De Franceschi, Marianna, additional, Fuchs, Claudia, additional, Bastianini, Stefano, additional, Viggiano, Rocchina, additional, Lupori, Leonardo, additional, Mazziotti, Raffaele, additional, Medici, Giorgio, additional, Lo Martire, Viviana, additional, Ren, Elisa, additional, Rimondini, Roberto, additional, Zoccoli, Giovanna, additional, Bartesaghi, Renata, additional, Pizzorusso, Tommaso, additional, and Ciani, Elisabetta, additional

Published
2018
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50. mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder

Author

Antonia Gurgone, Riccardo Pizzo, Alessandra Raspanti, Giuseppe Chiantia, Sunaina Devi, Debora Comai, Noemi Morello, Federica Pilotto, Sara Gnavi, Leonardo Lupori, Raffaele Mazziotti, Giulia Sagona, Elena Putignano, Alessio Nocentini, Claudiu T. Supuran, Andrea Marcantoni, Tommaso Pizzorusso, Maurizio Giustetto, Gurgone, Antonia, Pizzo, Riccardo, Raspanti, Alessandra, Chiantia, Giuseppe, Devi, Sunaina, Comai, Debora, Morello, Noemi, Pilotto, Federica, Gnavi, Sara, Lupori, Leonardo, Mazziotti, Raffaele, Sagona, Giulia, Putignano, Elena, Nocentini, Alessio, Supuran, Claudiu T, Marcantoni, Andrea, Pizzorusso, Tommaso, and Giustetto, Maurizio

Subjects
Pharmacology, Psychiatry and Mental health, Settore BIO/09 - Fisiologia
Abstract

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology. To this aim, we studied Class I metabotropic glutamate receptors 5 (mGluR5) because of their important role in the neuropathological signs produced by the lack of CDKL5 in-vivo, such as defective synaptogenesis, dendritic spines formation/maturation, synaptic transmission and plasticity. Importantly, mGluR5 function strictly depends on the correct expression of the postsynaptic protein Homer1bc that we previously found atypical in the cerebral cortex of Cdkl5-/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the binding strength of Homer1bc-mGluR5 complexes, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators (PAMs), i.e., 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioral defects shown by Cdkl5-/y mice. Notably, in the visual cortex of 2 CDD patients we found changes in synaptic organization that recapitulate those of mutant CDKL5 mice, including the reduced expression of mGluR5, suggesting that these receptors represent a promising therapeutic target for CDD.

Published
2022

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