A5076122435- Receptor Mechanisms and Signaling
- Axon Guidance and Neuronal Signaling
- Neuroscience and Neuropharmacology Research
- Neurogenesis and neuroplasticity mechanisms
- RNA Research and Splicing
- Bipolar Disorder and Treatment
- Genetics and Neurodevelopmental Disorders
- Nuclear Receptors and Signaling
- Protein Structure and Dynamics
- Cardiomyopathy and Myosin Studies
Broad Institute
2022-2024
Stanley Foundation
2023
Massachusetts Institute of Technology
2023
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 the NMDA receptor, greatly increase risk SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions neuronal (excitatory inhibitory) non-neuronal cells (astrocytes oligodendrocytes), (2) evidence...
Schizophrenia is a severe mental illness with high heritability, but its underlying mechanisms are poorly understood. We meta-analyzed large-scale brain transcriptomic data from mice harboring individual loss-of-function mutations in seven schizophrenia risk genes (Akap11, Dagla, Gria3, Grin2a, Sp4, Srrm2, Zmym2). While all studied regions were affected, the striatum and thalamus emerged as key of convergence. Striatum showed downregulation synapse- oxidative phosphorylation-related gene...
Abstract Rare loss-of-function (LoF) variants in SRRM2 , which encodes the splicing factor, are associated with schizophrenia and a neurodevelopmental disorder. How haploinsufficiency of leads to brain dysfunction is unknown. We find that Srrm2 +/- mice display (i) large-scale changes gene expression neuronal glial cells, affecting synapse-related other common molecular pathways across multiple regions, (ii) reduction key postsynaptic proteins, including gamma isoform SynGAP, itself encoded...
Loss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. We conducted multi-omic analyses Akap11 mutant mouse brains report neurobiological functions consequences its absence. interacts with multiple proteins involved signaling proteostasis. In Akap11+/- Akap11-/- synapses, PKA levels were markedly elevated, many synaptic hyperphosphorylated at substrate sites. showed extensive transcriptomic changes,...
SUMMARY Schizophrenia disease mechanisms remain poorly understood, in large part due to a lack of valid animal models. Rare heterozygous loss-of-function mutations GRIN2A , encoding subunit the NMDA (N-methyl-d-aspartate) receptor, greatly increase risk schizophrenia. By transcriptomic, proteomic, electroencephalogram (EEG) recording and behavioral analysis, we report that Grin2a mutant mice show: (i) large-scale gene expression changes across multiple brain regions neuronal (excitatory...
Abstract Schizophrenia and bipolar disorder are highly heritable mental illnesses with unclear pathophysiology. Heterozygous loss-of-function mutations of Sp4 , a zinc-finger transcription factor, greatly increase risk schizophrenia disorder. To investigate the molecular functions in an unbiased manner vivo we performed multi-omics analyses mutant mice. Bulk single nucleus RNA-seq data showed prominent gene expression changes all brain regions most cell types, including neuronal non-neuronal...
Schizophrenia disease mechanisms remain poorly understood, in large part due to lack of valid animal models. Rare heterozygous loss-of-function mutations GRIN2A, encoding a subunit the NMDA receptor, greatly increase risk schizophrenia. By transcriptomic, proteomic, electroencephalogram recording and behavioral analysis, we report that Grin2a mutant mice show: (i) large-scale gene expression changes across multiple brain regions neuronal (excitatory inhibitory) non-neuronal cells...