Substantial human brain development, particularly synaptic reorganization of the cerebral cortex, occurs postnatally. During the early postnatal period, normal cortical development is susceptible to disruption. Causes include primary insults (seizures, infection, injury), delayed effects of earlier perinatal damage (hypoxia/ischemia, fetal alcohol exposure, infections, e.g. AIDS), and genetically linked diseases (Down's syndrome, PKU, fragile X). These processes can lead to mental retardation and are associated with abnormal cortical synaptic architecture Thus, a first understanding of the cellular and molecular mechanisms that mediate development and refinement of cortical synapses is essential The development and modifiability of glutamate-mediated synaptic transmission in the cortex is a particularly critical process as these synapses are sensitive to structural and functional modification by early experience and they can contribute to neurotoxicity from over-activation. Cortical white matter (WM) neurons develop particularly early and they can contribute to neurotoxicity from over-activation. Cortical white matter (WM) neurons develop particularly early and play an important role in establishment of initial glutamatergic synaptic linkages. Until recently, it was assumed that during normal development, most of these WM neurons die. However, we now know that a substantial portion survives and innervates the overlying cortex throughout development. Moreover, many of the neurons express the enzyme for synthesizing nitric oxide (NO) which has been implicated in glutamate release, neurodevelopment, synaptic plasticity, and neurodegeneration. However, we know little about the functional properties or synaptic interactions of these surviving WM neurons or the role of NO in modulating glutamatergic synapses during development. Thus, we propose to elucidate the functional properties, the innervation pattern, the synaptic interactions of WOM neurons, and their ability to gate the throughput of glutamatergic synapses in the overlying neonatal cortex. We will also elucidate the developmental regulation of the signaling pathway where NO is produced and acts to modulate glutamate.
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