title: α7 Nicotinic receptor-mediated astrocytic gliotransmitter release: Aβ effects in a preclinical Alzheimer's mouse model.
abstract: It is now recognized that astrocytes participate in synaptic communication through intimate interactions with neurons. A principal mechanism is through the release of gliotransmitters (GTs) such as ATP, D-serine and most notably, glutamate, in response to astrocytic calcium elevations. We and others have shown that amyloid-β (Aβ), the toxic trigger for Alzheimer's disease (AD), interacts with hippocampal α7 nicotinic acetylcholine receptors (nAChRs). Since α7nAChRs are highly permeable to calcium and are expressed on hippocampal astrocytes, we investigated whether Aβ could activate astrocytic α7nAChRs in hippocampal slices and induce GT glutamate release. We found that biologically-relevant concentrations of Aβ1-42 elicited α7nAChR-dependent calcium elevations in hippocampal CA1 astrocytes and induced NMDAR-mediated slow inward currents (SICs) in CA1 neurons. In the Tg2576 AD mouse model for Aβ over-production and accumulation, we found that spontaneous astrocytic calcium elevations were of higher frequency compared to wildtype (WT). The frequency and kinetic parameters of AD mice SICs indicated enhanced gliotransmission, possibly due to increased endogenous Aβ observed in this model. Activation of α7nAChRs on WT astrocytes increased spontaneous inward currents on pyramidal neurons while α7nAChRs on astrocytes of AD mice were abrogated. These findings suggest that, at an age that far precedes the emergence of cognitive deficits and plaque deposition, this mouse model for AD-like amyloidosis exhibits augmented astrocytic activity and glutamate GT release suggesting possible repercussions for preclinical AD hippocampal neural networks that contribute to subsequent cognitive decline.
authors: School of Life and Health Sciences, Aston University, Birmingham, England.
authors: Tiina Maria
authors: TM
authors: Pirttimaki
authors: Neela Krushna
authors: NK
authors: Codadu
authors: Alia
authors: A
authors: Awni
authors: Pandey
authors: P
authors: Pratik
authors: David Andrew
authors: DA
authors: Nagel
authors: Eric James
authors: EJ
authors: Hill
authors: Kelly Tennyson
authors: KT
authors: Dineley
authors: H Rheinallt
authors: HR
authors: Parri
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D009457:Neuroglia / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D064569:alpha7 Nicotinic Acetylcholine Receptor; D018698:Glutamic Acid; D002118:Calcium