UC San Diego

Nicotinic cholinergic signaling acting through nicotinic acetylcholine receptors influences numerous cognitive functions including learning and memory. Critical for these higher brain functions are basic attributes of excitatory transmission that depend on proper trafficking and lateral mobility of glutamate receptors to and from synapses. The link between nicotinic signaling and glutamate receptor trafficking, however, remains unclear. Here we measure the effect of nicotine on the surface expression and lateral mobility of AMPA receptors on hippocampal neurons in culture. We find that a short exposure to nicotine for only a few hours leads to the stabilization and accumulation of GluR1-containing AMPA receptors on dendritic spines. This process occurs through direct action on postsynaptic nicotinic acetylcholine receptors, independent of coincident fast, excitatory synaptic transmission, and results in increased synaptic efficacy. The pathway relies on intracellular calcium signaling, PDZ interactions, and the lateral diffusion, but not exocytosis, of GluR1-containing AMPA receptors. Prolonging the nicotine exposure by a few days, however, leads to the destabilization of AMPA receptors on spines. This is measured as an increase in the mobility of GluR2- containing AMPA receptors. Surprisingly, we find that nicotinic agonists alone, in the absence of nicotine, have the same effect on GluR2-containing AMPA receptor mobility, suggesting a non-canonical nicotinic mechanism. Our results demonstrate that varied nicotinic manipulations can have profound effects on glutamate receptor trafficking and offer insight into the possible mechanisms underlying the cognitive effects of nicotinic signaling