Department of Physiology and Biophysics

RESEARCH

Nicotinic acetylcholine receptors (nAChRs) are widespread in the mammalian, where they mediate nicotine addiction and are thought to be neuroprotective. While this receptor system has been the target of therapies for neurodegenerative diseases like Alzheimer’s disease, very little is known about what their roles might be in brain functions. Using multiple approaches, we address this question from a number of angles

Nicotinic receptors in the hippocampus

In the mammalian hippocampus, an area important in memory and learning, nAChRs are present on presynaptic terminals of glutamatergic and GABAergic synapses. Here they modulate the release of these transmitters, thus regulating synaptic plasticity. We are examining the mechanism underlying nAChR-mediated glutamate release at the mossy fiber-CA3 pyramidal cell synapse. These are large complex boutons (see figure below) that contain multiple active zones.

Legend: A diI stained granule cell showing a long axon interrupted by bead-like mossy fiber boutons. Scale bar 10 mm.

Activation of nAChRs results in a store calcium-mediated increase in the frequency of glutamate release at this synapse and a calcium/calmodulin kinase II-dependent synchronized release of multiple quanta. This powerful regulation of glutamate release can drive transmission at this synapse in the absence of incoming presynaptic action potentials, suggesting that nicotine can ‘hijack’ this synapse modulating it in the absence of physiological context but in a manner dependent on the presence of this drug of abuse.

In addition, nAChRs are also present on postsynaptic neurons, as well as astrocytes. Our current efforts are to understand how this receptor controls the excitability of the CA3 network by pre- and post-synaptic mechanisms as well as via the modulation of interactions between neurons and astrocytes.

Nicotinic receptors in the Olfactory bulb

Cholinergic systems affect the ability of an animal to learn to discriminate between two closely related odors. We use electrophysiology and imaging techniques to understand how the cholinergic system regulates the output of the olfactory bulb in order to make this learnt discrimination possible. We find that at the site where the input from the nose arrives, a neuropil structure, called the glomerulus, nAChRs act as gatekeepers, controlling the efficacy, timing and sensitivity of synaptic information.

Legend: The glomerular circuitry. Inputs from the nose arrive at the glomerulus. In this structure, excitatory neurons (external tufted cells; ET) and inhibitory neurons (periglomerular neurons; PG) process the information and control the excitation of the principal neurons, the mitral cells.

Cholinergic transmission

While cholinergic deficit is thought to be primary in the etiology of neurodegenerative disorders, very little is known about the mechanics of cholinergic transmission in the brain. We use a transgenic mouse model, where cholinergic axons are labeled with a tauGFP fusion protein, to visualize individual fibers in live brain slices, to examine synaptic and extrasynaptic signaling by cholinergic neurons.

Legend: Cholinergic neurons and their processes in the medial habenula from a tauGFP transgenic mouse.