Your browser doesn't support javascript.
loading
Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice.
Farsi, Zohreh; Nicolella, Ally; Simmons, Sean K; Aryal, Sameer; Shepard, Nate; Brenner, Kira; Lin, Sherry; Herzog, Linnea; Moran, Sean P; Stalnaker, Katherine J; Shin, Wangyong; Gazestani, Vahid; Song, Bryan J; Bonanno, Kevin; Keshishian, Hasmik; Carr, Steven A; Pan, Jen Q; Macosko, Evan Z; Datta, Sandeep Robert; Dejanovic, Borislav; Kim, Eunjoon; Levin, Joshua Z; Sheng, Morgan.
Afiliação
  • Farsi Z; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: zfarsi@broadinstitute.org.
  • Nicolella A; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Simmons SK; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Aryal S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Shepard N; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Brenner K; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lin S; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
  • Herzog L; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Moran SP; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Stalnaker KJ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Shin W; Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea.
  • Gazestani V; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Song BJ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bonanno K; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Keshishian H; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Carr SA; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Pan JQ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Macosko EZ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
  • Datta SR; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
  • Dejanovic B; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kim E; Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea; Department of Biological Sciences, Korea Advanced Institute for Science and Technology, Daejeon, South Korea.
  • Levin JZ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sheng M; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: msheng@broadinstitute.org.
Neuron ; 111(21): 3378-3396.e9, 2023 11 01.
Article em En | MEDLINE | ID: mdl-37657442
ABSTRACT
A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Dopamina / Receptores de N-Metil-D-Aspartato / Proteômica Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Dopamina / Receptores de N-Metil-D-Aspartato / Proteômica Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article