A functional cerebral cortex is essential for virtually all higher order behavioral processes including sensorimotor integration, cognition, use of language and reasoning. The quintessential feature of cerebral cortex is its highly laminated structure with cascades of serial feed-forward and feed-back innervation. The development of the mammalian neocortex is characterized by a number of distinctive (but highly interactive) cellular processes in neurons and glia. Epigenetic factors that interfere with any of these processes in the fetus and/or neonate (such as hypoxia, exposure to infectious agents, environmental toxins, alcohol/drug exposure, nutritional deficits or an impoverished sensory/cognitive environment) are likely to result in a functionally compromised cerebral cortex, often with profound consequences for cognitive development. The overall goal of this project is to define the mechanisms that mediate certain key events in the normal development of the cerebral cortex. In particular, the major excitatory (those that use glutamate as a neurotransmitter) neuronal pathways in the cerebral cortex will be studied with respect to neuronal synaptogenesis, differentiation of the myelin-producing oligodendrocytes and the regulation of neuronal glutamate release. A relatively newly discovered gaseous molecule -- nitric oxide (NO) -- has been suggested to play a major role in the development, refinement and regulation of synaptic architecture and synaptic efficacy in the central nervous system (CNS), including the cerebral cortex. The proposed experiments will address the role of this molecule in the development and refinement of cortical glutamatergic synapses, the differentiation of functional oligodendrocytes, and the regulation of the release of glutamate - the major excitatory neurotransmitter that also can act as an excitotoxin, during postnatal development of the cerebral cortex.
The aims of the project are to evaluate the role of nitric oxide in i) the development of synapse formation, ii) myelinogenesis and iii) glutamate release, respectively. The first part will evaluate the morphological development of NO generating circuitry in the cortex and the ability of NO to influence cortical neuron neurite outgrowth and synaptogenesis. The second part will evaluate the role of NO in the differentiation of immature oligodendrocytes into functional myelin forming cells. The third part will evaluate the development of NO signaling in the cortex and its ability to modulate glutamate release.
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