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In JoVE (1)
Other Publications (8)
- The Journal of Clinical Investigation
- Molecular and Cellular Biology
- Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology
- Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology
- Asian Journal of Andrology
- Zhonghua Nan Ke Xue = National Journal of Andrology
- Zhonghua Nan Ke Xue = National Journal of Andrology
- PloS One
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Articles by Shao-Ming Lu in JoVE
JoVE Neuroscience
जीर्ण दो photon के लिए एक पतली खोपड़ी विंडो तकनीक Vivo में Murine microglia Neuroinflammation के मॉडल में इमेजिंग
1Center for Neural Development and Disease, Department of Neurology, Child Neurology Division, University of Rochester, 2Department of Neurobiology and Anatomy, University of Rochester
हम बार बार murine microglia visualizing और monocytes परिसंचारी के लिए एक विधि का वर्णन
Other articles by Shao-Ming Lu on PubMed
Synaptic Activity Becomes Excitotoxic in Neurons Exposed to Elevated Levels of Platelet-activating Factor
Neurologic impairment in HIV-1-associated dementia (HAD) and other neuroinflammatory diseases correlates with injury to dendrites and synapses, but how such injury occurs is not known. We hypothesized that neuroinflammation makes dendrites susceptible to excitotoxic injury following synaptic activity. We report that platelet-activating factor, an inflammatory phospholipid that mediates synaptic plasticity and neurotoxicity and is dramatically elevated in the brain during HAD, promotes dendrite injury following elevated synaptic activity and can replicate HIV-1-associated dendritic pathology. In hippocampal slices exposed to a stable platelet-activating factor analogue, tetanic stimulation that normally induces long-term synaptic potentiation instead promoted development of calcium- and caspase-dependent dendritic beading. Chemical preconditioning with diazoxide, a mitochondrial ATP-sensitive potassium channel agonist, prevented dendritic beading and restored long-term potentiation. In contrast to models invoking excessive glutamate release, these results suggest that physiologic synaptic activity may trigger excitotoxic dendritic injury during chronic neuroinflammation. Furthermore, preconditioning may represent a novel therapeutic strategy for preventing excitotoxic injury while preserving physiologic plasticity.
NF-kappaB/Rel Regulates Inhibitory and Excitatory Neuronal Function and Synaptic Plasticity
Changes in synaptic plasticity required for memory formation are dynamically regulated through opposing excitatory and inhibitory neurotransmissions. To explore the potential contribution of NF-kappaB/Rel to these processes, we generated transgenic mice conditionally expressing a potent NF-kappaB/Rel inhibitor termed IkappaBalpha superrepressor (IkappaBalpha-SR). Using the prion promoter-enhancer, IkappaBalpha-SR is robustly expressed in inhibitory GABAergic interneurons and, at lower levels, in excitatory neurons but not in glia. This neuronal pattern of IkappaBalpha-SR expression leads to decreased expression of glutamate decarboxylase 65 (GAD65), the enzyme required for synthesis of the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) in GABAergic interneurons. IkappaBalpha-SR expression also results in diminished basal GluR1 levels and impaired synaptic strength (input/output function), both of which are fully restored following activity-based task learning. Consistent with diminished GAD65-derived inhibitory tone and enhanced excitatory firing, IkappaBalpha-SR+ mice exhibit increased late-phase long-term potentiation, hyperactivity, seizures, increased exploratory activity, and enhanced spatial learning and memory. IkappaBalpha-SR+ neurons also express higher levels of the activity-regulated, cytoskeleton-associated (Arc) protein, consistent with neuronal hyperexcitability. These findings suggest that NF-kappaB/Rel transcription factors act as pivotal regulators of activity-dependent inhibitory and excitatory neuronal function regulating synaptic plasticity and memory.
Protecting the Synapse: Evidence for a Rational Strategy to Treat HIV-1 Associated Neurologic Disease
Loss of synaptic integrity and function appears to underlie neurologic deficits in patients with HIV-1-associated dementia (HAD) and other chronic neurodegenerative diseases. Because synaptic injury often long precedes neuronal death and surviving neurons possess a remarkable capacity for synaptic repair and functional recovery, we hypothesize that therapeutic intervention to protect synapses has great potential to improve neurologic function in HAD and other diseases. We discuss findings from both HAD and Alzheimer's disease to demonstrate that the disruption of synaptic structure and function that can occur during excitotoxic injury and neuroinflammation represents a likely substrate for neurologic deficits. Based on available evidence, we provide a rationale for future studies aimed at identifying molecular targets for synaptic protection in neurodegenerative disease. Whereas patients with HAD beginning antiretroviral therapy have shown reversal of neurologic symptoms that is unique for patients with chronic neurodegenerative conditions, we propose that the potential for such reversal is not unique.
The Phospholipid Mediator Platelet-activating Factor Mediates Striatal Synaptic Facilitation
The phospholipid mediator platelet-activating factor (PAF), an endogenous modulator of glutamatergic neurotransmission, can also be secreted by brain mononuclear phagocytes during HIV-1 infection. Platelet-activating factor can induce neuronal apoptosis by NMDA receptor-dependent and independent mechanisms. We now demonstrate that acute administration of sublethal doses of PAF to striatal slices augments synaptic facilitation in striatal neurons following high-frequency stimulation, which can be blocked by PAF receptor antagonists, suggesting that striatal synaptic facilitation can be augmented by PAF receptor agonism. We also demonstrate that repeated sublethal doses of PAF during tetanic stimulation can greatly increase the magnitude of postsynaptic potentials and action potentials, but a lethal dose of PAF destroys the capacity of corticostriatal synapses to achieve this augmented synaptic facilitation. Thus, the relative concentration and temporal pattern of PAF expression at glutamatergic synapses may govern whether it acts in a physiologic or pathophysiologic manner during striatal neurotransmission.
Early Apoptotic Changes in Human Spermatozoa and Their Relationships with Conventional Semen Parameters and Sperm DNA Fragmentation
To investigate whether early apoptotic changes in spermatozoa can be significant markers for sperm quality.
[Effects of Two Different Cryoprotectants on the Motility of Post-thaw Human Sperm]
To compare the effects of the cryoprotectant containing glucose and that containing sucrose on the motility of post-thaw human sperm.
[Use of L-carnitine Before Percutaneous Epididymal Sperm Aspiration-intracytoplasmic Sperm Injection for Obstructive Azoospermia]
To explore the use of L-carnitine before percutaneous epididymal sperm aspiration-intracytoplasmic sperm injection (PESA-ICSI) in the treatment of obstructive azoospermia.
HIV-1 Tat-induced Microgliosis and Synaptic Damage Via Interactions Between Peripheral and Central Myeloid Cells
Despite the ability of combination antiretroviral treatment (cART) to reduce viral burden to nearly undetectable levels in cerebrospinal fluid and serum, HIV-1 associated neurocognitive disorders (HAND) continue to persist in as many as half the patients living with this disease. There is growing consensus that the actual substrate for HAND is destruction of normal synaptic architecture but the sequence of cellular events that leads to this outcome has never been resolved. To address whether central vs. peripheral myeloid lineage cells contribute to synaptic damage during acute neuroinflammation we injected a single dose of the HIV-1 transactivator of transcription protein (Tat) or control vehicle into hippocampus of wild-type or chimeric C57Bl/6 mice genetically marked to distinguish infiltrating and resident immune cells. Between 8-24 hr after injection of Tat, invading CD11b(+) and/or myeloperoxidase-positive leukocytes with granulocyte characteristics were found to engulf both microglia and synaptic structures, and microglia reciprocally engulfed invading leukocytes. By 24 hr, microglial processes were also seen ensheathing dendrites, followed by inclusion of synaptic elements in microglia 7 d after Tat injection, with a durable microgliosis lasting at least 28 d. Thus, central nervous system (CNS) exposure to Tat induces early activation of peripheral myeloid lineage cells with phagocytosis of synaptic elements and reciprocal microglial engulfment of peripheral leukocytes, and enduring microgliosis. Our data suggest that a single exposure to a foreign antigen such as HIV-1 Tat can lead to long-lasting disruption of normal neuroimmune homeostasis with deleterious consequences for synaptic architecture, and further suggest a possible mechanism for enduring neuroinflammation in the absence of productive viral replication in the CNS.
