Wang H, Song L, Lee A, Laird F, Wong PC, Lee HK.
Mossy fiber long-term potentiation deficits in BACE1 knock-outs can be rescued by activation of alpha7 nicotinic acetylcholine receptors.
J Neurosci. 2010 Oct 13;30(41):13808-13.
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In this manuscript, Wang et al. detail an investigation into a presynaptic form of NMDA-independent LTP (mfLTP) at the mossy fiber—CA3 synapse in mice lacking β-secretase (BACE1)—BACE KO. They report that the mfLTP deficits can be rescued by activation of the Aα7 nicotinic acetylcholine receptor (nAChR). The rescue depends upon calcium-induced calcium release (CICR), presumably from activation of the highly calcium-permeable presynaptic Aα7 nAChRs. This is an interesting finding, since it appears that wild-type (WT) mfLTP does not depend upon Aα7 nAChR activation; it is not enhanced with nicotine treatment or diminished by Aα7 nAChR antagonist in WT hippocampal slices. As well, in WT slices, mfLTP is only partly dependent upon CICR, since blockade of the ryanodine receptor, which is crucial for CICR, incompletely inhibits mfLTP. In addition, BACE KO mice exhibit no alterations in baseline synaptic transmission, and Aα7 nAChR rescue of mf LTP is not through alterations in baseline synaptic transmission, suggesting that Aα7 nAChRs do not participate in glutamate neurotransmitter release at these synapses.
These observations suggest that, in the absence of BACE, the coupling of Aα7 nAChRs to CICR is significantly enhanced, either through augmentation of Aα7 nAChR function and calcium influx, or localization so that the receptors are in closer proximity to the ryanodine-sensitive calcium stores. The former mechanism could be tested by measuring calcium signals at mossy fiber synapses comparing nicotine stimulation of slices from WT versus BACE KO mice in the presence of CICR and voltage-gated calcium channel blockade. If Aα7 nAChR function is potentiated in the BACE KOs, then one would predict that nicotine-induced calcium signals are greater in BACE KO samples. If no difference is detected, this would indicate a mechanism involving altered trafficking and localization of Aα7 nAChRs within presynaptic mossy fibers, such that Aα7 nAChRs more efficiently couple to CICR. Moreover, this suggests that, under normal circumstances, when BACE is expressed within the Golgi and trafficked within the endosomal compartment that cycles to and from the cell surface along with APP and the γ-secretase, the presynaptic Aα7 nAChR population is not positioned to contribute to mfLTP, further suggesting that BACE, or BACE interaction with APP, influences the subcellular localization of Aα7 nAChRs. Therefore, in the absence of BACE, relocated Aα7 nAChRs are capable of improved coupling to CICR.
Why suggest such a mechanism? Although Wang et al. did not observe alterations in the ratio of surface:total Aα7 nAChRs, the methodology employed would not have revealed changes in surface membrane localization (e.g., axonal, peri-synaptic, presynaptic). Our work has revealed that amyloid precursor protein (APP) Tg2576 mice lacking Aα7 nAChRs have altered APP processing such that BACE processing of the APP is reduced when Aα7 nAChRs are absent (Hernandez et al., 2010). This was in the absence of any influence on BACE proteolytic activity. We interpreted these data to suggest that Aα7 nAChRs potentially influence APP trafficking, since APP processing is highly dependent upon the cellular compartment within which it resides. The findings of Wang et al. (2010) reveal an alternative interpretation: that Aα7 nAChRs and BACE reciprocally modulate the others’ subcellular location.
Hernandez CM, Kayed R, Zheng H, Sweatt JD, Dineley KT.
Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease.
J Neurosci. 2010 Feb 17;30(7):2442-53.