Our laboratory uses genetic techniques to study the role of neuromodulators in the development and function of the mammalian nervous system. Most neuromodulators are polypeptides or amino acid derivatives. They are packaged in synaptic vesicles and released into the synaptic cleft upon neuronal stimulation where they modulate the activity of neurons by binding to membrane receptors coupled to G-protein-linked signaling pathways.
Our laboratory has been studying the role of the catecholamines, norepinephrine and dopamine, by making mice in which enzymes required for their biosynthesis have been inactivated. Mice that cannot make norepinephrine die as embryos, apparently due to cardiac failure; however, they can be rescued to birth pharmacologically, after which time they develop quite normally without further intervention. These norepinephrine-deficient mice display a number of interesting behavioral and metabolic differences from controls that are currently being investigated. Mice that cannot synthesize dopamine develop normally but die a few weeks after birth due to a hypoactivity and a failure to eat or drink. They can be maintained with L-DOPA , a precursor to dopamine. When treated with L-DOPA, the mice become hyperactive and sexually aggressive. The dopamine requirement for normal feeding behavior is a major focus of our attention.
We have also inactivated the gene encoding neuropeptide Y (NPY),a neuropeptide that is expressed in both the central and peripheral nervous systems. These mice are particularly interesting to us because NPY has been implicated in feeding behavior because injection of this peptide into the brain stimulates voracious feeding; however, mice that cannot synthesize NPY feed normally. We are currently seeking the explanation for the discrepancy between the pharmacological and the genetic results. The last neuromodulator under study is zinc! Zinc is packaged with glutamate in some neurons in the central nervous system and they are released together in response to stimulation. Because both glutamate and GABA receptor functions are modulated by zinc in vitro, it has been proposed that zinc may be an important neuromodulator. We are testing this hypothesis by inactivating a gene that codes for the transporter necessary foruptake of zinc into synaptic vesicles. These knockout mice will provide the first clues about the potential role of synaptic zinc as a neuromodulator.