A5057444811- Neuroscience and Neuropharmacology Research
- Neural dynamics and brain function
- Photoreceptor and optogenetics research
- Functional Brain Connectivity Studies
- Neuroinflammation and Neurodegeneration Mechanisms
- CRISPR and Genetic Engineering
- Receptor Mechanisms and Signaling
- Memory and Neural Mechanisms
- RNA Research and Splicing
- Retinal Development and Disorders
- Virus-based gene therapy research
- RNA Interference and Gene Delivery
- Cellular transport and secretion
- RNA and protein synthesis mechanisms
- Animal Behavior and Reproduction
- Advanced biosensing and bioanalysis techniques
- Mitochondrial Function and Pathology
- Neuroscience and Neural Engineering
- Alzheimer's disease research and treatments
- Neurobiology and Insect Physiology Research
- Neural and Behavioral Psychology Studies
- Tryptophan and brain disorders
- Neuroendocrine regulation and behavior
- Neurotransmitter Receptor Influence on Behavior
- Pancreatic function and diabetes
Johns Hopkins Medicine
2020-2023
Johns Hopkins University
2019-2023
Discovery Institute
2020-2023
University of Oxford
2014-2019
University of Bristol
2017
Abstract It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination genetically modified mice where obligatory NMDAR-subunit GluN1 (also known as NR1) deleted PV by Cre -mediated knockout corresponding gene Grin1 ( ΔPV mice). Notably, such PV-specific ablation reported blunt induction hyperlocomotion (a surrogate for psychosis)...
Elucidating how synaptic molecules such as AMPA receptors mediate neuronal communication and tracking their dynamic expression during behavior is crucial to understand cognition disease, but current technological barriers preclude large-scale exploration of molecular dynamics in vivo. We have developed a suite innovative methodologies that break through these barriers: new knockin mouse line with fluorescently tagged endogenous receptors, two-photon imaging hundreds thousands labeled...
The efficient knock-in of large DNA fragments to label endogenous proteins remains especially challenging in non-dividing cells such as neurons. We developed Targeted Knock-In with Two (TKIT) guides a novel CRISPR/Cas9 based approach for efficient, and precise, genomic knock-in. Through targeting non-coding regions TKIT is resistant INDEL mutations. demonstrate labeling synaptic various tags, efficiencies up 42% mouse primary cultured Utilizing utero electroporation or viral injections mice...
Abstract Increased fronto-temporal theta coherence and failure of its stimulus-specific modulation have been reported in schizophrenia, but the psychological correlates underlying neural mechanisms remain elusive. Mice lacking putative schizophrenia risk gene GRIA1 ( Gria1 –/– ), which encodes GLUA1, show strongly impaired spatial working memory elevated selective attention owing to a deficit short-term habituation. A habituation has suggested cause an aberrant assignment salience thereby...
Clathrin-mediated endocytosis (CME) is used to internalize a diverse range of cargo proteins from the cell surface, often in response specific signals. In neurons, rapid GluA2-containing AMPA receptors (AMPARs) NMDA receptor (NMDAR) stimulation causes reduction synaptic strength and central mechanism for long-term depression, which underlies certain forms learning. The mechanisms that link NMDAR activation CME AMPARs remain elusive. PICK1 BAR domain protein required NMDAR-dependent...
Abstract Precise and reliable cell-specific gene delivery remains technically challenging. Here we report a splicing-based approach for controlling expression whereby separate translational reading frames are coupled to the inclusion or exclusion of mutated, frameshifting alternative exons. Candidate exons identified by analyzing thousands publicly available RNA sequencing datasets filtering cell specificity, conservation, local intron length. This method, which denote splicing-linked design...
Pathological over-activity of the CA1 subfield human anterior hippocampus has been identified as a potential predictive marker for transition from prodromal state to overt schizophrenia. Psychosis, in turn, is associated with elevated activity subiculum, hippocampal output stage directly activated by CA1. Over-activity these subfields may represent useful endophenotype guide translationally preclinical models. To recreate this and study its causal relation deficits positive cognitive symptom...
Significance Throughout an organism’s life span, neural circuits mediate sensory and cognitive processing via synaptic plasticity, which involves synapse-specific Hebbian plasticity network-level homeostatic plasticity. Synaptic strengthening weakening are finely tuned by changes in postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) -type glutamate receptors (AMPARs). We have elucidated a biochemical regulation of AMPARs that is specific to while sparing mechanisms....
Abstract Background Communication between brain areas has been implicated in a wide range of cognitive and emotive functions is impaired numerous mental disorders. In rodent models, various metrics have used to quantify inter-regional neuronal communication. However, individual studies, typically, only very few measures coupling are reported and, hence, redundancy across such indicators implicitly assumed. Results order test this assumption, we here comparatively assessed broad directional...
Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that agonist LY354740 appeared to rescue cognitive deficits caused by non-competitive N-methyl-d-aspartate (NMDAR) antagonists, including spatial working memory rodents. Here, we tested ability of performance mice lack GluA1 subunit AMPA receptor, encoded Gria1, a gene recently implicated schizophrenia genome-wide association studies. We found failed...
Synapses in the brain exhibit cell-type-specific differences basal synaptic transmission and plasticity. Here, we evaluated specializations composition of glutamatergic synapses, identifying Btbd11 as an inhibitory interneuron-specific, synapse-enriched protein. is highly conserved across species binds to core postsynaptic proteins, including Psd-95. Intriguingly, show that can undergo liquid-liquid phase separation when expressed with Psd-95, supporting idea density synapses interneurons...
The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands proteins and is key node in the regulation synaptic plasticity. To gain new mechanistic insight into experience-induced changes PSD, we examined global dynamics hippocampal PSD proteome phosphoproteome mice following four different types experience. Mice were trained using an inhibitory avoidance (IA) task fractions isolated from individual to investigate molecular mechanisms...
Interactions between genetic and environmental risk factors take center stage in the pathology of schizophrenia. We assessed if stressor reduced enrichment applied adulthood provokes deficits positive, negative or cognitive symptom domains schizophrenia a mouse line modeling NMDA-receptor (NMDAR) hypofunction forebrain inhibitory interneurons (Grin1 ΔPpp1r2 ). find that Grin1 mice, when group-housed highly enriched cages, appear largely normal across wide range schizophrenia-related...
Abstract Elucidating how synaptic molecules such as AMPA receptors mediate neuronal communication and tracking their dynamic expression during behavior is crucial to understand cognition disease, but current technological barriers preclude large-scale exploration of molecular dynamics in vivo. We have developed a suite innovative methodologies that break through these barriers: new knockin mouse line with fluorescently tagged endogenous receptors, two-photon imaging hundreds thousands...
SUMMARY Synapses in the brain exhibit cell-type-specific differences basal synaptic transmission and plasticity. Here, we evaluated composition of glutamatergic synapses, identifying Btbd11, as an inhibitory interneuron-specific synapse-enriched protein. Btbd11 is highly conserved across species binds to core postsynaptic proteins including Psd-95. Intriguingly, show that can undergo liquid-liquid phase separation when expressed with Psd-95, supporting idea post density synapses excitatory...
Phosphatidic acid is a key signaling molecule heavily implicated in exocytosis due to its protein-binding partners and propensity induce negative membrane curvature. One phosphatidic acid-producing enzyme, phospholipase D (PLD), has also been neurotransmission. Unfortunately, the unreliability of reagents, there confusion literature regarding expression PLD isoforms mammalian brain which hampered our understanding their functional roles neurons. To address this, we generated epitope-tagged...
Abstract Working memory (WM), the capacity to briefly and intentionally maintain mental items, is key successful goal-directed behaviour impaired in a range of psychiatric disorders. To date, several brain regions, connections, types neural activity have been correlatively associated with WM performance. However, no unifying framework integrate these findings exits, as degree their species- task-specificity remains unclear. Here, we investigate correlates three task paradigms each mice...
Abstract The efficient knock-in of large DNA fragments to label endogenous proteins remains especially challenging in non-dividing cells such as neurons. We developed T argeted K nock- I n with wo-guides (TKIT) a novel CRISPR/Cas9 based approach for efficient, and precise, genomic knock-in. Through targeting non-coding regions TKIT is resistant INDEL mutations. demonstrate labelling synaptic various tags, efficiencies up 42% mouse primary cultured Utilizing utero electroporation or viral...
ABSTRACT Communication between brain areas has been implicated in a wide range of cognitive and emotive functions is impaired numerous mental disorders. In rodent models, various functional connectivity metrics have used to quantify inter-regional neuronal communication. However, individual studies, typically only very few measures coupling are reported and, hence, redundancy across such indicators implicitly assumed. order test this assumption, we here comparatively assessed broad...
Abstract Precise and reliable cell-specific gene delivery remains technically challenging. Here we report a splicing-based approach for controlling expression whereby separate translational reading frames are coupled to the inclusion or exclusion of alternative exons. Candidate exons identified by analyzing thousands publicly available RNA sequencing datasets filtering cell specificity, sequence conservation, local intron length. This method, which denote splicing-linked design (SLED), can...
Summary The post synaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands proteins and is key node in the regulation plasticity. To gain new mechanistic insight into experience-induced changes PSD, we examined global dynamics PSD proteome phosphoproteome mice following various treatments. Mice were trained using an inhibitory avoidance (IA) task hippocampal fractions isolated for quantitative proteomic phosphoproteomics analysis. We used...