A5075749828- Genetics and Neurodevelopmental Disorders
- Neural dynamics and brain function
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Congenital heart defects research
- Neurobiology and Insect Physiology Research
- Circadian rhythm and melatonin
- RNA Research and Splicing
- Birth, Development, and Health
- Tryptophan and brain disorders
- Protein Structure and Dynamics
- Neurogenesis and neuroplasticity mechanisms
- Neuroscience and Music Perception
- Neuroendocrine regulation and behavior
- Photoreceptor and optogenetics research
- Nuclear Receptors and Signaling
- Paranormal Experiences and Beliefs
- Neurotransmitter Receptor Influence on Behavior
- Earth Systems and Cosmic Evolution
- Cardiomyopathy and Myosin Studies
- Transcranial Magnetic Stimulation Studies
- Memory and Neural Mechanisms
- Plant and Biological Electrophysiology Studies
- Diet and metabolism studies
- Space Science and Extraterrestrial Life
Broad Institute
2022-2024
Stanley Center for Psychiatric Research
2022
Harvard University
2016-2021
Howard Hughes Medical Institute
2016
The University of Texas at Austin
2013
Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We use quantitative mass spectrometry to carry out deep, unbiased proteomic profiling synapses purified from dorsolateral prefrontal cortex 35 cases SCZ, BP, controls. Compared with controls, SCZ BP show substantial similar alterations. Network analyses reveal upregulation proteins associated autophagy certain vesicle transport pathways downregulation related synaptic, mitochondrial,...
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...
Abstract Schizophrenia is a heterogeneous psychiatric disorder with strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including mutations in GRIN2A (aka GluN2A or NR2A , encoding the NMDA receptor subunit 2A) AKAP11 (A-Kinase Anchoring Protein 11). are also associated bipolar [2], epilepsy developmental delay/intellectual disability [1, 3,...
When presented with a light cue followed by food, some rats simply approach the foodcup (Nonorienters), while others first orient to in addition displaying food-cup behavior (Orienters). Cue-directed orienting may reflect enhanced attentional and/or emotional processing of cue, suggesting divergent natures cue-information Orienters and Nonorienters. The current studies investigate how differences might manifest appetitive memory retrieval updating using paradigm developed persistently...
Daily physical remodeling of neurons changes the internal sense daytime and nighttime.
Loss-of-function mutations in ZMYM2 are associated with an increased risk of schizophrenia (SCZ) and neurodevelopmental disorders (NDD). interacts proteins involved histone modification gene regulation, including LSD1 ADNP; however, its specific roles the brain remain poorly understood. In this multi-omics study, we demonstrate that heterozygous knockout Zmym2 mice results widespread disturbances expression affecting diverse molecular pathways, those related to modifications neuronal...
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...
A-Kinase Anchoring Protein 11 (AKAP11) is a shared genetic risk factor for schizophrenia and bipolar disorder, yet its role in the brain remains poorly understood. Through multi-omic analysis of Akap11 mutant mouse brains cultured astrocytes, we identified significant transcriptomic, proteomic, metabolomic alterations. Key findings include upregulation cholesterol fatty acid metabolic pathways, accumulation lipid species such as cholesteryl esters, triacylglycerols, ceramides,...
ABSTRACT BACKGROUND Schizophrenia is a heterogeneous psychiatric disorder with strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including mutations in GRIN2A (aka GluN2A or NR2A , encoding the NMDA receptor subunit 2A) AKAP11 (A-Kinase Anchoring Protein 11). are also associated bipolar [2], epilepsy developmental delay/intellectual [1, 3,...
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,...
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...
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...
Ongoing sensations are compared to internal, experience-based, reference models; mismatch between reality and expectation can signal opportunity or danger, shape behavior. The nature of internal models is largely unknown. We describe a model that enables moment-to-moment luminance evaluation in flies. Abrupt shifts lighting conditions inconsistent with the subjective time-of-day trigger locomotion, whereas appropriate induce quiescence. prediction generated by slowly shifting activity...
Abstract Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We used quantitative mass-spectrometry to carry out deep unbiased profiling proteome synapses purified from dorsolateral prefrontal cortex 35 cases SCZ, BP, controls. Compared controls, SCZ BP showed substantial similar proteomic alterations. Network gene set enrichment analyses revealed upregulation proteins associated with autophagy certain vesicle transport pathways,...