Nicotinic receptors at GABAergic synapses in the hippocampus
Initial Award Abstract
Nicotine, the primary addictive compound in tobacco, achieves its effects by acting through proteins in the membrane called nicotinic receptors. These receptors are widely distributed and serve many roles. They have also been implicated in a number of neuropathologies, including Alzheimer's disease, schizophrenia, and Parkinson's disease. One of the most abundant and multi-potent nicotinic receptors is a species composed of the 7 gene product. These 7-receptors are highly permeable to calcium and regulate a variety of calcium-dependent events. They are particularly abundant in the hippocampus, a tissue that is required for the brain to encode new memories. Previous work has shown that 7-receptors are found both on the upstream and downstream side of numerous synapses (connections between neurons where signaling occurs) in the hippocampus. The receptors are thought to change the strength of signaling that occurs at such synapses. The receptors are expressed at their highest levels in the hippocampus during the first few weeks postnatally in mammals, and preliminary evidence suggests that at this time the receptors may be preferentially concentrated on the downstream side of synapses using the chemical GABA for signaling. This is a critical issue because during early postnatal life, GABA signaling is actually excitatory rather than inhibitory as it is throughout the mature adult brain. The significance of this is that stimulation by nicotine early in development may inappropriately accentuate the excitatory GABA signaling in the neonatal brain and may even produce long-lasting effects. Nicotine delivery to the neonatal brain could come either from mother's milk or from second-hand smoke.
The initial experiments proposed here will replicate and extend preliminary evidence suggesting that 7-receptors are preferentially concentrated at GABA synapses. A variety of techniques will be used to determine whether nicotinic stimulation of the receptors accentuates GABA signaling when it is excitatory, and whether chronic nicotinic stimulation produces long-lasting changes in the GABA signal. Of particular interest is the possibility that chronic nicotinic stimulation alters the developmental time course for conversion of GABA signaling capability from excitatory to inhibitory. Preliminary results suggest that septal input down-regulates 7-receptors to levels found in the adult. Tiny extensions tipped with 7-receptor clusters can be found on hippocampal neurons and may serve as precursor structures for synaptic contacts. This too will be examined by a variety of techniques.
The proposed experiments will provide important new information about the role of nicotinic receptors in early brain function and development. The results are likely to indicate substantial hazards posed by chronic nicotine exposure in the very young. This information will help the biomedical scientist in understanding the neurological consequences of smoking and will help the public evaluate the cost and danger of tobacco usage. |