Patricia M. Whitaker-Azmitia
Associate Professor
PhD Univ. Toronto
Alice Borella - Research Specialist
James Bell - Graduate Student
My laboratory studies the neuro-developmental role of serotonin. Thus, we were the first to describe its role in autoregulating the development of the neurons in which serotonin is produced. In these studies, we have described the role of presynaptic receptors (probably related to the 5-HT1b receptor) in inhibiting outgrowth and of astroglial receptors (the 5-HT1a receptor) in promoting outgrowth. Astroglial 5-HT1a receptors release the calcium binding
protein and neurite extension factor, S-100. In turn, S-100 increases growth of serotonergic neurons and promotes neurite extension in serotonergic target areas such as hippocampus and cortex. Our most recent developmental studies have looked at the effects of serotonin depletion during peak synaptogenesis in the rat. As adults, these animals have fewer synapses ( as indicated by the markers MAP-2 and synaptophysin). As well, the animals
appear to be less capable of synaptic plasticity (as indicated by decreased GAP-43 staining as well as by three different behavioral models of learning and memory).
Recently, we have become increasingly aware of the likelihood that serotonin still releases S-100 in the mature brain, and that it thus still plays a role in regulating synaptic density in its target regions. Our hypothesis states that by inhibiting the production of cAMP (through the 5-HT1a receptor on neurons) serotonin inhibits the phosphorylation of MAP-2 which leads to microtubule dissociation and loss of dendrites. The S-100 released by the astroglial 5-HT1a receptor inhibits the phosphorylation of GAP-43, allowing continued growth of the presynaptic terminal. Thus, through actions on both neuronal and astroglial 5-HT1a receptors, serotonin leads to an increased synaptic density. We are currently studying the actions of serotonin as a trophic molecule in the adult brain, and thus its role in mental illnesses and their treatment by psychoactive drugs.
Relevant Publications:
Whitaker-Azmitia, P.M., Zhang, X. and Clarke, C. (1994). Effects of gestational exposure to monoamine oxidase inhibitors in rats. Neuropsychopharm. 11(2):125-132.
Whitaker-Azmitia, P.M., Borella, A. and Raio, N. (1995). Serotonin depletion in the adult rat causes loss of the dendritic marker MAP-2: A new animal model of schizophrenia? Neuropsychopharm.12(3):269-272.
Whitaker-Azmitia, P.M., Druse, M., Walker, P. and Lauder, J.M. (1996). Serotonin as a developmental signal. Behavioral Brain Research, 73:19-29.
Clarke, C., Clarke, K., Muneyyirci, J., Azmitia, E. and Whitaker-Azmitia, P.M. (1996). Prenatal cocaine delays astroglial maturation: immunodensitometry shows increased markers of immaturity (vimentin and GAP-43) and decreased proliferation and production of the growth factor S-100. Dev. Brain Research, 91:268-273.