Assessing the coupling between local neural activity and global connectivity fluctuations: Application to human intracranial electroencephalography during a cognitive task

Cognitive-relevant information is processed by different brain areas that cooperate to eventually produce a response. The relationship between local activity and global brain states during such processes, however, remains for the most part unexplored. To address this question, we designed a simple face-recognition task performed in patients with drug-resistant epilepsy and monitored with intracranial electroencephalography (EEG). Based on our observations, we developed a novel analytical framework (named “local–global” framework) to statistically correlate the brain activity in every recorded gray-matter region with the widespread connectivity fluctuations as proxy to identify concurrent local activations and global brain phenomena that may plausibly reflect a common functional network during cognition. The application of the local–global framework to the data from three subjects showed that similar connectivity fluctuations found across patients were mainly coupled to the local activity of brain areas involved in face information processing. In particular, our findings provide preliminary evidence that the reported global measures might be a novel signature of functional brain activity reorganization when a stimulus is processed in a task context regardless of the specific recorded areasPeer ReviewedPostprint (published version

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.Fil: Salpietro, Vincenzo. Università degli Studi di Genova; Italia. University College London; Estados UnidosFil: Malintan, Nancy T.. Università degli Studi di Genova; ItaliaFil: Llano Rivas, Isabel. Hospital Universitario Cruces; EspañaFil: Spaeth, Christine G.. University of Cincinnati; Estados UnidosFil: Efthymiou, Stephanie. University College London; Estados UnidosFil: Striano, Pasquale. Istituto Giannina Gaslini; Italia. University of Genoa; ItaliaFil: Vandrovcova, Jana. University College London; Estados UnidosFil: Cutrupi, Maria Concetta. University of Messina; ItaliaFil: Chimenz, Roberto. University of Messina; ItaliaFil: David, Emanuele. Papardo University Hospital; ItaliaFil: Di Rosa, Gabriella. University of Messina; ItaliaFil: Marce Grau, Anna. University Hospital Vall d’Hebron; EspañaFil: Raspall Chaure, Miquel. University Hospital Vall d’Hebron; EspañaFil: Martin Hernandez, Elena. Hospital 12 de Octubre; EspañaFil: Zara, Federico. Istituto Giannina Gaslini; ItaliaFil: Minetti, Carlo. Istituto Giannina Gaslini; ItaliaFil: Bello, Oscar Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: De Zorzi, Rita. Università degli Studi di Trieste; ItaliaFil: Fortuna, Sara. Università degli Studi di Trieste; ItaliaFil: Dauber, Andrew. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Alkhawaja, Mariam. No especifíca;Fil: Sultan, Tipu. Institute of Child Health and The Children’s Hospital Lahore; PakistánFil: Mankad, Kshitij. Great Ormond Street Hospital for Children; Reino UnidoFil: Vitobello, Antonio. Center Hospitalier Universitaire Dijon Bourgogne; FranciaFil: Thomas, Quentin. Center Hospitalier Universitaire Dijon Bourgogne; FranciaFil: Tran Mau Them, Frederic. Center Hospitalier Universitaire Dijon Bourgogne; FranciaFil: Faivre, Laurence. Hospital d’Enfants, Dijon; Francia. Center Hospitalier Universitaire Dijon Bourgogne; FranciaFil: Martinez Azorin, Francisco. No especifíca;Fil: Prada, Carlos E.. University of Cincinnati; Estados UnidosFil: Macaya, Alfons. University Hospital Vall d’Hebron; Españ

Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (<i>PPP1R3F</i>) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic features

Abstract PPP1R3F (R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures, and other neurological findings including tone, gait, and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization, and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.</jats:p