EXCEED THE SPACE PROVIDED. We recently discovered that embryonic and neonatal cortical neurons express functional glycine receptors (GlyR) in abundance. Furthermore, we found that the endogenous agonist for the cortical GlyR is the amino acid taurine. Taurine is known to be concentrated at very high levels in the developing neocortex and is suspected to play an important role in corticogenesis. Taurine deficiency in utero produces severe brain malformation associated with disordered migration and differentiation of cortical neurons. Animal studies strongly suggest that taurine deprivation might also produce brain malformations in humans, and as a result taurine is now added to infant formulae. However, the mechanism of taurine's important effect on brain development has not been explored. Our discovery of a receptor for taurine forms the basis of this proposal to study the mechanism of action of taurine and its role in regulating brain development. We will use in vitro culture systems and electrophysiological and neuroanatomical methods to test the hypothesis that the effects of taurine on neuronal migration and differentiation are mediated through GlyRs. In preliminary experiments, we found that GlyR activation is excitatory in immature neurons and leads to elevation of intracellular free calcium. We will use pharmacological methods to test the hypothesis that the developmental effects of taurine are mediated by second messenger cascades triggered by this signal. Because the long-term effects of taurine are likely to result from transcription of growth-related genes, we will use molecular biologicaltechniques to examine changes in gene expression induced by GlyR activation. This proposal thus represents the initial examination of a novel excitatory transmitter system active in the developing neocortex and implicated in the production of a severe cortical malformation. PERFORMANCE SITE ========================================Section End===========================================
| Noctor, Stephen C; Martinez-Cerdeno, Veronica; Ivic, Lidija et al. (2004) Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7:136-44 |
| Weissman, Tamily; Noctor, Stephen C; Clinton, Brian K et al. (2003) Neurogenic radial glial cells in reptile, rodent and human: from mitosis to migration. Cereb Cortex 13:550-9 |
| Ivic, Lidija; Sands, Tristan T J; Fishkin, Nathan et al. (2003) Terpene trilactones from Ginkgo biloba are antagonists of cortical glycine and GABA(A) receptors. J Biol Chem 278:49279-85 |
