Biology subjects

Medici, G.

Publications and source records attributed to Medici, G..

3 recordsLinked to original sources

bioRxiv2024

Postnatal Sensory Experience and Barrel Cortex Alterations Anticipate Autistic Traits in a Mouse Model of Cdkl5 Deficiency Disorder

Autistic traits may arise from atypical sensory experience during postnatal life, but whether there is a causal link between defects in cortical circuitry in the brain, altered sensory processing and social behavior remains unknown. Here, we studied tactile stimuli processing in the barrel cortex (BC) and social interactions in juvenile male mice lacking Cyclin-dependent kinase-like 5 (CDKL5), a model of a severe neurodevelopmental disease showing autistic traits and sensory impairments. We identified in these mice defects of whisker-dependent postnatal sensorimotor reflexes, NMDA receptors-dependent signaling, and dendritic orientation in thalamic inputs-receiving spiny stellate neurons. We also found that CDKL5 is required for mapping and processing whisker-derived tactile stimuli in the BC. Intriguingly, KO mice show autistic traits at p21 that are rescued by neonatal CDKL5 replacement in the BC. Our data suggest that CDKL5 is required to link tactile processing in the BC to the onset of social interaction abilities.

neuroscience↗

bioRxiv2023

Integrative spatial analysis reveals a multi-layered organization of glioblastoma

Glioma contains malignant cells in diverse states. Hypoxic regions are associated with a unique histology of pseudopalisading cells, while other regions appear to have limited histological organization, reflecting the diffuse nature of glioma cells. Here, we combine spatial transcriptomics with spatial proteomics and novel computational approaches to define glioma cellular states at high granularity and uncover their organization. We find three prominent modes of cellular organization. First, cells in any given state tend to be spatially clustered, such that tumors are composed of small local environments that are each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. Despite the unique composition of each tumor, this pairing of states remains largely consistent across tumors. Third, the pairwise interactions that we detect collectively define a global architecture composed of five layers. Hypoxia appears to drive this 5-layered organization, as it is both associated with unique states of surrounding cells and with a long-range organization that extends from the hypoxic core to the infiltrative edge of the tumor. Accordingly, tumor regions distant from any hypoxic foci and tumors that lack hypoxia such as IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of gliomas at the resolution of cellular states and highlight the role of hypoxia as a long-range tissue organizer.

cancer biology↗

bioRxiv2021

EXPRESSION OF A SECRETABLE, CELL-PENETRATING CDKL5 PROTEIN ENHANCES THE EFFICACY OF AAV VECTOR-MEDIATED GENE THERAPY FOR CDKL5 DEFICIENCY DISORDER.

No therapy is currently available for CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the CDKL5 gene. Although delivery of a wild-type copy of the mutated gene to cells represents the most curative approach for a monogenic disease, proof-of-concept studies highlight significant efficacy caveats for brain gene therapy. Herein, we used a secretable TATk-CDKL5 protein to enhance the efficiency of a gene therapy for CDD. We found that, although AAVPHP.B_Igk-TATk-CDKL5 and AAVPHP.B_CDKL5 vectors had similar brain infection efficiency, the AAVPHP.B_Igk-TATk-CDKL5 vector led to a higher CDKL5 protein replacement due to secretion and transduction of the TATk-CDKL5 protein into the neighboring cells. Importantly, Cdkl5 KO mice treated with the AAVPHP.B_Igk-TATk-CDKL5 vector showed a behavioral and neuroanatomical improvement in comparison with vehicle-treated Cdkl5 KO mice or Cdkl5 KO mice treated with the AAVPHP.B_CDKL5 vector, indicating that a gene therapy based on a secretable recombinant TATk-CDKL5 protein is more effective at compensating Cdkl5-null brain defects than gene therapy based on the expression of the native CDKL5.

neuroscience↗