Grant: $231,000 - National Institutes of Health - Sep. 29, 2009
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Award Description: Over the last 4 years the parent grant (HD 44517) has been focused on improving our understanding of the pathophysiology of anesthesia-induced developmental neurodegeneration so that effective neuroprotective strategies can be developed. Our work, done with funding by the parent grant, has shown that mitochondria are likely to be the most vulnerable initial intracellular target of anesthesia neurotoxicity and, as such, have an important role in initiating the intrinsic apoptotic pathway that leads to the activation of caspases, DNA fragmentation and significant neuronal death. Aside from their control of neuroapoptosis, mitochondria are important for normal neuronal development and functioning. Of particular interest for this supplement is the fact that mitochondria constantly migrate within the cytoplasm. This leads to a change in their subcellular distribution so that they can be strategically positioned in the vicinity of active growth cones of developing neurons, in axon terminals with active synapses, and in dendritic spines. Our recent findings suggest that general anesthesia causes a Significant decrease in synapse density, impairment of synaptic neurotransmission, and mitochondrial morphogenesis in vulnerable brain regions such as the subiculum, a part of the hippocampal proper. Based on our pilot findings, it appears that a significantly higher percentage of mitochondria-containing presynaptic profiles occurs in control subiculum than in anesthesia-treated one. In addition, experimental mitochondrial profiles were significantly larger than control profiles, although the ratio between mitochondrial area and the area of mitochondria-containing presynaptic nerve terminals was about the same in control and experimental subiculums. This suggests that the swollen and possibly sluggish mitochondria get stuck in more proximal neuronal processes and cannot effectively migrate to small, distant synaptic contacts. This, in turn, may prevent distant synaptic contacts from receiving adequate and timely metabolic support. If, indeed, the strategic presence of mitochondria in the vicinity of functionally active synapses is crucially important during brain development, it is possible that the observed neurotoxic effects of general anesthesia are caused, at least in part, by impairment of mitochondrial regional distribution. This could result in a scarcity of mitochondria in dendritic branches and in proximity to synaptic boutons when and where they are most needed. To investigate the effects of general anesthesia on mitochondrial motility, we propose to study the pathophysiology and mechanisms of anesthesia-induced impairment of intraneuronal mitochondrial trafficking. RELEVANCE (See instructions): Clinically used general anesthetics are damaging to developing mammalian brain. Since the use of general anesthetics often cannot be avoided, a better understanding of the key mechanisms of anesthesia-induced developmental neurotoxicity and ways to ameliorate their effects are of great importance. Using in-vitro systems, this supplement aims to identify the mechanisms involved in the impairment of mitochondrial motility and trafficking as a potential cause of anesthesia-induced disturbances in synaptogenesis.
Project Description: See Award Description;
Jobs Summary: None (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 29, 2009. Help expand these official descriptions using the wiki below.