A5084536873- Mitochondrial Function and Pathology
- Neuroscience and Neuropharmacology Research
- ATP Synthase and ATPases Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Tryptophan and brain disorders
- Stress Responses and Cortisol
- Genetics and Neurodevelopmental Disorders
- Neurogenesis and neuroplasticity mechanisms
- Cell death mechanisms and regulation
- Nuclear Receptors and Signaling
- CRISPR and Genetic Engineering
- RNA Interference and Gene Delivery
- Virus-based gene therapy research
- Cellular transport and secretion
- Neural dynamics and brain function
- Anesthesia and Neurotoxicity Research
- Animal Vocal Communication and Behavior
- Apelin-related biomedical research
- Signaling Pathways in Disease
- RNA regulation and disease
- Macrophage Migration Inhibitory Factor
- Autophagy in Disease and Therapy
- Ion channel regulation and function
- Metabolism and Genetic Disorders
- Genomic variations and chromosomal abnormalities
Yale University
2015-2024
McGill University
2023
University of New Haven
2018
Connecticut Mental Health Center
2012
Harvard University Press
2010
Max Planck Institute for Medical Research
2004-2007
Max Planck Society
2006
University College London
2004
Significance Stressful cellular events cause intracellular Ca 2+ dysregulation, rapid loss of inner mitochondrial membrane potential [the permeability transition (PT)], metabolic dysfunction, and death. Rapid -induced uncoupling is one the most important regulators cell demise. We show that c-subunit ring F 1 O ATP synthase forms a voltage-sensitive channel, persistent opening which leads to PT In contrast, channel closure promotes survival increased efficiency metabolism. The therefore...
It is becoming increasingly clear that single cortical neurons encode complex and behaviorally relevant signals, but efficient means to study gene functions in small networks vivo are still lacking. Here, we establish a method for genetic manipulation subsequent phenotypic analysis of individual vivo. First, lentiviral vectors used neuron-specific delivery from alpha-calcium/calmodulin-dependent protein kinase II or Synapsin I promoters, optionally combination with knockdown by U6...
The gene encoding the forkhead box transcription factor, FOXP2, is essential for developing full articulatory power of human language. Mutations FOXP2 cause developmental verbal dyspraxia (DVD), a speech and language disorder that compromises fluent production words correct use comprehension grammar. patients have structural functional abnormalities in striatum basal ganglia, which also express high levels FOXP2. Since learned vocalizations songbirds bear behavioral neural parallels, provide...
Abstract Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that binds directly the F 1 O ATP synthase β subunit. DJ-1’s interaction with subunit decreased mitochondrial uncoupling and enhanced production efficiency while in contrast or knockout increased uncoupling, depolarized neuronal mitochondria. In mesencephalic KO cultures, there was a progressive loss of process extension. This ameliorated by pharmacological reagent, dexpramipexole,...
Decreased neuronal dendrite branching and plasticity of the hippocampus, a limbic structure implicated in mood disorders, is thought to contribute symptoms depression. However, mechanisms underlying this effect, as well actions antidepressant treatment, remain poorly characterized. Here, we show that hippocampal expression neuritin, an activity-dependent gene regulates plasticity, decreased by chronic unpredictable stress (CUS) treatment reverses effect. We also viral-mediated neuritin...
Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well post-traumatic (PTSD). The molecular mechanisms underlying structural and functional alterations within corticolimbic brain regions, including prefrontal cortex (PFC) amygdala individuals subjected traumatic stress, remain unknown. In this study, we show that serum glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in postmortem PFC PTSD subjects. Furthermore, demonstrate...
Abstract Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) patients with depression and rodent chronic stress models. Here, we examine consequences PFC GFAP+ cell depletion activity enhancement on depressive-like behaviors rodents. Using viral expression diphtheria toxin receptor cells, which allows experimental these cells following administration, demonstrated that induced anhedonia-like behavior within 2 days...
The efficacy of excitatory transmission in the brain depends to a large extent on synaptic AMPA receptors, hence importance understanding delivery and recycling receptors at sites. Here we report novel regulation receptor transport by PDZ (postsynaptic density-95/ Drosophila disc tumor suppressor zona occludens 1) LIM (Lin11/rat Isl-1/Mec3) domain-containing protein, RIL (reversion-induced protein). We show that binds glutamate subunit GluR-A C-terminal peptide via its domain α-actinin...
Two adjacent groups of midbrain dopaminergic neurons, A9 (substantia nigra pars compacta) and A10 (ventral tegmental area), have distinct projections exhibit differential vulnerability in Parkinson's disease.Little is known about transcription factors that influence subgroup phenotypes or their potential role disease.Here, we demonstrate elevated expression the factor orthodenticle homeobox 2 neurons embryonic adult mouse, primate human midbrain.Overexpression using lentivirus increased...
B-cell lymphoma-extra large (Bcl-xL) protects survival in dividing cells and developing neurons, but was not known to regulate growth. Growth synapse formation are indispensable for neuronal development, inextricably linking these processes. We have previously shown that, during synaptic plasticity, Bcl-xL produces changes number, size, activity, mitochondrial metabolism. In this study, we determine whether is required healthy neurite outgrowth necessary neurons the presence or absence of...
ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis cancer cells by occupying BH3-binding pocket. We have shown previously that lowers cell metabolic efficiency inhibiting ATP synthase activity. However, we also found protects rodent brain from ischemic injury in vivo formation pro-apoptotic, cleaved form Bcl-xL, ΔN-Bcl-xL. now report high concentration (1 μM), or more selective Bcl-xL WEHI-539 (5 μM)...
Fragile X syndrome (FXS) is the leading known inherited intellectual disability and most common genetic cause of autism. The full mutation results in transcriptional silencing Fmr1 gene loss fragile mental retardation protein (FMRP) expression. Defects neuroenergetic capacity are to a variety neurodevelopmental disorders. Thus, we explored integrity forebrain mitochondria knockout mice during peak synaptogenesis. We found inefficient thermogenic respiration due futile proton leak KO caused...
Neuronal activity stimulates mRNA translation crucial for learning and development. While FMRP (Fragile X Mental Retardation Protein) CYFIP1 (Cytoplasmic FMR1 Interacting Protein 1) regulate translation, the mechanism linking to neuronal is not understood. We now find that stimulated when translocate potassium channel Slack (KCNT1, Slo2.2). When activated, both factors are released from eIF4E (Eukaryotic Initiation Factor 4E), where they normally inhibit initiation. A constitutively active...
GABBR1 and GABBR2 are widely expressed in the brain genetic inhibition of their function leads to widespread neurologic dysfunction premature death mice. Given that heterodimerize form a functional receptor, global knockout or results similar phenotype, characterized by spontaneous epileptiform activity, hyperlocomotor hyperalgesia, impaired memory death. It is now known both variety tissues outside nervous system GABA-B receptors can with other class C GPCRs, including extracellular...
B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, accumulation ∆N-Bcl-xL causes dysfunction neuronal death. In this study, we hypothesized that generation reactive oxygen species (ROS) during excitotoxicity leads formation ∆N-Bcl-xL. We further proposed...