Examinando por Autor "Brauer, Bastian"

Mostrando 1 - 4 de 4
  • No hay miniatura disponible
    Ítem
    Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior
    (BMC Biology,Volume 22, Issue 1 December 2024, Article number 142, 2024-12) Ahumada-Marchant, Constanza; Ancatén-Gonzalez, Carlos; Haensgen, Henny; Brauer, Bastian; Merino-Veliz, Nicolas; Droste, Rita; Arancibia, Felipe; Horvitz, H. Robert; Constantine-Paton, Martha; Arriagada, Gloria; Chávez, Andrés E.; Bustos, Fernando J.
    Background: The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown. Results: To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments. Conclusions: We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions. © The Author(s) 2024.
  • No hay miniatura disponible
    Ítem
    Impact of KDM6B mosaic brain knockout on synaptic function and behavior
    (Scientific Reports, Volume 14, Issue 1 December 2024, Article number 20416, 2024-11) Brauer, Bastian; Ancatén-González, Carlos; Ahumada-Marchant, Constanza; Meza, Rodrigo C.; Merino-Veliz, Nicolas; Nardocci, Gino; Varela-Nallar, Lorena; Arriagada, Gloria; Chávez, Andrés E.; Bustos, Fernando J.
    Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions. © The Author(s) 2024.
  • No hay miniatura disponible
    Ítem
    Impact of KDM6B mosaic brain knockout on synaptic function and behavior
    (Nature, 0024-12) Brauer, Bastian; Ancatén-González, Carlos; Ahumada-Marchant, Constanza; Meza, Rodrigo C.; Merino-Veliz, Nicolas; Nardocci, Gino; Varela-Nallar, Lorena; Arriagada, Gloria; Chávez, Andrés E.; Bustos, Fernando J.
    Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions. © The Author(s) 2024.
  • No hay miniatura disponible
    Ítem
    KMT2C knockout generates ASD-like behaviors in mice
    (Frontiers Media SA, 2023) Brauer, Bastian; Merino-Veliz, Nicolas; Ahumada-Marchant, Constanza; Arriagada, Gloria; Bustos, Fernando J.
    Neurodevelopmental disorders have been associated with genetic mutations that affect cellular function, including chromatin regulation and epigenetic modifications. Recent studies in humans have identified mutations in KMT2C, an enzyme responsible for modifying histone tails and depositing H3K4me1 and H3K4me3, as being associated with Kleefstra syndrome 2 and autism spectrum disorder (ASD). However, the precise role of KMT2C mutations in brain disorders remains poorly understood. Here we employed CRISPR/Cas9 gene editing to analyze the effects of KMT2C brain specific knockout on animal behavior. Knocking out KMT2C expression in cortical neurons and the mouse brain resulted in decreased KMT2C levels. Importantly, KMT2C brain specific knockout animals exhibited repetitive behaviors, social deficits, and intellectual disability resembling ASD. Our findings shed light on the involvement of KMT2C in neurodevelopmental processes and establish a valuable model for elucidating the cellular and molecular mechanisms underlying KMT2C mutations and their relationship to Kleefstra syndrome 2 and ASD. Copyright © 2023 Brauer, Merino-Veliz, Ahumada-Marchant, Arriagada and Bustos.