Nicotinic Control of Glutamate Synapse Formation
Initial Award Abstract
Nicotine is the major substance in tobacco that mediates addiction and alters the function of the nervous system. It does this by acting on specific proteins on the surfaces of cells in the brain. These proteins are called nicotinic acetylcholine receptors (nAChRs) and are widely distributed throughout the brain and spinal cord. Normally nAChRs are activated by a small molecule present in the brain and they function to control a variety of events and brain activity. Behavioral consequences of this kind of signaling (called nicotinic cholinergic signaling) includes effects on cognition, memory formation, and arousal. Nicotinic cholinergic signaling has also been associated with numerous pathologies including Alzheimer's disease, schizophrenia, and addiction.
Recent work from our group has shown that ongoing normal nicotinic cholinergic activity is necessary for brain development involving the formation of specific connections called glutamate synapses. Because glutamate synapses make up most of the excitatory connections in the nervous system, their proper formation and maturation are critical for brain function. The new results show that nicotinic activity exerts its effects on glutamate synapses by going through two pathways. The main pathway, and the one that is most interesting, is one that employs nAChRs made up of proteins called α7-subunits, hence the name α7-nAChRs. Normal stimulation of these α7-nAChRs is required for glutamate synapses to mature and become functional on schedule. Even more surprising, long-term exposure to nicotine in the brain can accelerate and amplify the process, generating more synapses. How α7-nAChRs do this is unknown. This proposal is designed to answer that question and assess the consequences of nicotine exposure.
Our preliminary results unexpectedly show that a different cell type in brain, namely those called astrocytes, are likely to mediate at least part of the α7-nAChR effect on glutamate synapse formation. Astrocytes are a major class of cells in the mammalian brain but are not thought to participate directly in electrical signaling. They are abundant, however, and are closely associated with many kinds of connections, including glutamate synapses. Because of this they can participate in a variety of brain functions, contributing to the timing, location, number, and function of synapses. Astrocytes also express a variety of nAChR subunits including α7. Our results suggest that nicotinic stimulation of astrocytes causes them to release component(s) that can increase the number of glutamate synapse-like contacts formed between neurons.
This project begins by determining how nicotine induces astrocytes to exert this effect, and goes on to determine how stable and functional the newly formed glutamate synapses are. Subsequent experiments determine whether there is also a separate mechanism originating from α7-nAChR on the cells that actually form the synapses (neurons) and whether the outcomes produced by those receptors can be different from that achieved via astrocytes. The final section of the proposal examines the consequences of the α7-nAChR effect directly, examining predicted changes in signaling between neurons and their ability to participate in changes thought to be associated with the learning process.
These experiments are designed to not only determine the pathways through which nicotinic stimulation of α7-nAChRs affects development of glutamate synapses but also to assess the impact both short- and long-term for system function. The results are likely to provide new insight into basic mechanisms critical for normal development and indicate their vulnerability to manipulation by repeated exposure to nicotine. This information will indicate dangers of early exposure and may suggest targets for compensatory intervention. |