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

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.This work has been supported by grant GR-2017–02364378 funded by the Italian Ministry of Health and by Telethon grant GGP19177 to LB; Italian Ministry of Health, RC 2021; grant from Fondazione Cassa di Risparmio di Firenze “Human Brain Optical Mapping” to TP; grants from the Spanish Ministry of Science and Innovation (MICINN) co-financed by ERDF (grant no. RTI2018-102260-B-I00; Generalitat Valenciana, project no. PROMETEO/2020/007; and CSIC Interdisciplinary Thematic Platform (PTI +) NEURO-AGINGl + (PTI-NEURO-AGING +). C.M.N-I. was the recipient of a FPI fellowship from the MICINN. The Instituto de Neurociencias (UMH-CSIC) is a “Centre of Excellence Severo Ochoa” (grant no. SEV-2017–0723).Peer reviewe

Luni e il territorio di Massa tra il Tardoantico e gli inizi del Medioevo

Si contestualizza l’insediamento tardoantico/altomedievale di Massa nel quadro dell’assetto di Luni e del suo territorio nello stesso periodo, con riferimento alle vicende economiche, politiche e sociali

Massa tra l’età romana e il Medioevo

Nei secoli che a Luni vedono la diffusione del cristianesimo, a Massa l’abitato che si imposta sui resti di un complesso produttivo di età repubblicana e imperiale attraversa i secoli della tarda antichità tra la dominazione bizantina e quella longobarda. Le testimonianze ceramiche documentano ancora per il V e il VI secolo il suo inserimento in una rete commerciale di dimensione mediterranea, verosimilmente mediata da Luni, mentre, tra VI e VII secolo, le relazioni appaiono ridimensionate a un ambito regionale

Un insediamento tardo-antico e alto-medievale nell’ager lunensis: gli scavi di piazza Mercurio a Massa

Nel centro storico di Massa, in un territorio afferente in epoca romana alla colonia di Luni, indagini condotte tra il 2011 e il 2012 in occasione della ripavimentazione di Piazza Mercurio hanno permesso di doumentare una complessa stratificazione che rimonta fino all’età arcaica. Stratificazioni e materiali attestano la presenza nell’area anche di un abitato tardoantico altomedievale compreso tra IV e VII secolo d.C. Se fino alla fine del V e agli inizi del VI secolo I reperti ceramici attestano un quadro variegato nella circolazione dei diversi prodotti, a partire dalla metà del VI secolo si assiste ad un picco negativo delle importazioni: evidentemente la guerra tra Bizantini e Longobardi e la successiva conquista di parte della Tuscia provocò la cesura dei traffici transmarini e un generale ripiegamento del mercato sulle produzioni locali

La platea mercatalis. Periodo VI. Bassomedioevo

Sequenza stratigrafica delle fasi bassomedievali dello scavo di Piazza del Mercurio a Mass

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

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