Nicotinic Regulation of GABAergic Signaling
Initial Award Abstract
Nicotine, the addictive component of tobacco, has numerous effects in the nervous system, in addition to promoting the addiction itself. A surprising new development is that nicotine may access key pathways that control major transitions in the developing nervous system. It is now widely accepted that brain chemicals such GABA and glycine, which normally cause inhibition or a quieting down of brain networks, actually have the opposite effect in the developing fetus and newborn. During this early period, GABA and glycine excite the networks. The excitatory phase of these chemicals is essential for normal development. They appear to determine, in part, how the cells of the nervous system extend branches and receive connections from other cells. If, on the other hand, the transition to the inhibitory phase did not properly occur, it also would have disastrous effects. At the very least the system would be vulnerable to monumental epileptic seizures; death would be almost certain.
We find, quite unexpectedly, that this key transition from GABA excitation to GABA inhibition appears to be under the control of pathways that nicotine stimulates. Blockade of the pathways delays the transition from GABA excitation to inhibition, and that in turn appears to have significant consequences for the cells and connections of the developing nervous system. Moreover, even neurons newly born in the adult brain from precursor cells display the same transitions, and may also be vulnerable to perturbation by nicotine.
This proposal will examine the key pathways responsible for the transition of GABA from being excitatory to being inhibitory. It will examine the underlying mechanisms and the cells at risk. Further, the proposal will examine the consequences of perturbing normal activity in the pathways during development. It will do this by combining a number of cellular and molecular approaches, and manipulating activity in the pathways responding to nicotine. This will provide new information about fundamental processes in the developing fetus and neonate affected by nicotine.
The experiments define new areas and may potentially change how we think about the wiring up of the nervous system. The biomedical implications are also significant. If these pathways have the kinds of pervasive effect in development that the preliminary results suggest, early exposure to nicotine would be a very serious matter. Indirect exposure of the fetus or newborn to nicotine, e.g. nicotine either in the maternal blood or milk or airborne via tobacco smoke, could have deleterious effects, activating the pathways inappropriately or desensitizing them so that normal signaling is impaired. The developing nervous system would be uniquely vulnerable to this exposure if in fact these pathways normally play a broad instructional role at early times. |
|Sequential interplay of nicotinic and GABAergic signaling guides neuronal development.
|Authors: Liu Z, Ness RA, Berg DK