Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency
| Autor: | Elsa Ghirardini, Giulia Sagona, Angel Marquez-Galera, Francesco Calugi, Carmen M. Navarron, Francesco Cacciante, Siwei Chen, Federica Di Vetta, Lorenzo Dadà, Raffaele Mazziotti, Leonardo Lupori, Elena Putignano, Pierre Baldi, Jose P. Lopez-Atalaya, Tommaso Pizzorusso, Laura Baroncelli |
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| Přispěvatelé: | 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, Baroncelli, Laura |
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
Creatine transporter deficiency
Clinical Sciences Neurodegenerative Settore BIO/09 - Fisiologia Pathology and Forensic Medicine Cellular and Molecular Neuroscience Mice Neurodevelopmental disorder Genetics Animals 2.1 Biological and endogenous factors Aetiology Neurons Brain Diseases Epilepsy Parvalbumin neuron Neurodevelopmental disorders Neurosciences Membrane Transport Proteins Energy metabolism Creatine Synapse Brain Disorders Inborn Parvalbumins Neurological Neurology (clinical) Metabolic Biochemistry and Cell Biology Parvalbumin neurons |
| Zdroj: | Acta neuropathologica communications, vol 11, iss 1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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