The effect of α7 nicotinic receptor activation on glutamatergic transmission in the hippocampus

Abstract

Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory, however the cellular mechanism of these actions remains elusive. With help from newly developed biosensors and optogenetic tools, recent studies provide new insights on signaling mechanisms involved in the activation of nAChRs. Here we will review α7 nAChR's action in the tri-synaptic pathway in the hippocampus. The effects of α7 nAChR activation via either exogenous compounds or endogenous cholinergic innervation are detailed for spontaneous and evoked glutamatergic synaptic transmission and synaptic plasticity, as well as the underlying signaling mechanisms. In summary, α7 nAChRs trigger intracellular calcium rise and calcium-dependent signaling pathways to enhance glutamate release and induce glutamatergic synaptic plasticity.

Keywords: Calcium; Glutamatergic transmission; Hippocampus; cAMP; α7 Nicotinic acetylcholine receptor.

Figure 1

Mechanisms of α7 nAChR-mediated presynaptic enhancement of glutamate release. The intracellular calcium level at presynaptic terminals is increased by calcium influx through α7 nAChRs, VGCCs, and NMDARs from the outside, and calcium release from intracellular calcium stores. The raised calcium levels could increase vesicular glutamate release directly, and trigger cAMP-PKA-dependent pathways for prolonged enhancement of glutamate release. Phosphorylation of synapsins by PKA leads to synaptic vesicle mobilization from the reserve pool to the readily releasable pool, hence increasing glutamate release. (Purple trapeziods depict unphosphorylated synapsins, while red trapezoids depict phosphorylated synapsins.)