Acetylcholine is considered to be an important neurotransmitter in the mammalian brain, and behavioral phenomena such as attention, learning and memory, nociception, and nicotine addiction are all thought to involve cholinergic systems. Furthermore, cholinergic deficits have been implicated in disorders such as Alzheimer's disease and schizophrenia. Despite the fact that a great deal is known about cholinergic systems in general, very little is known about synaptic transmission in the brain mediated via nicotinic receptors. Hippocampal interneurons receive a fast, excitatory input via nicotinic synapses that are sensitive to the snake toxin, alpha-bungarotoxin, suggesting that the postsynaptic receptors at these synapses contain the nicotinic alpha-7 receptor subunit. The proposed experiments will investigate fundamental issues relating to neurotransmission at these nicotinic synapses. The first objective of these experiments will be to determine the source of the presynaptic cholinergic fibers that innervate hippocampal interneurons. Although most evidence suggests that the cholinergic synapses on CA1 interneurons arise from septal cholinergic neurons, there is evidence that some or all of these synapses could be made by putative intrinsic hippocampal cholinergic neurons. A second objective of this application will be to characterize the pharmacological and physiological properties of nicotinic synapses onto CA1 neurons.

Very little is known about how these nicotinic synapses respond to repetitive activation, how rapidly they desensitize, whether they are affected by presynaptic modulators, and whether there are more persistent effects on interneurons that are mediated via CA2+ influx through these Ca2+-permeable ion channels. The final objective of these experiments will be to characterize the projections of interneurons that can be activated by alpha-7 nicotinic receptors. We will characterize the projections of interneurons that can be activated by alpha-7 nicotinic receptors both electrophysiologically, by recording responses from their target neurons (pyramidal neurons, and other interneurons), and morphologically, by labeling interneurons that receive nicotinic input with biocytin, and reconstructing their axonal projections. By answering these fundamental questions, it will be possible to integrate what we know about these nicotinic synapses into the much larger body of knowledge concerning the role played by interneurons in regulating hippocampal activity, and the way in which cholinergic activity controls the function of this key population of hippocampal neurons.

R01MH061617

2001-02-01

2003-07-31