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α7 Nicotinic receptor-mediated astrocytic gliotransmitter release: Aβ effects in a preclinical Alzheimer's mouse model.

Pirttimaki TM, Codadu NK, Awni A, Pratik P, Nagel DA, Hill EJ, Dineley KT, Parri HR - PLoS ONE (2013)

Bottom Line: 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 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).

View Article: PubMed Central - PubMed

Affiliation: School of Life and Health Sciences, Aston University, Birmingham, England.

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.

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Aβ1-42-mediated astrocytic activation is α7nAChR mediated.A. Fluorescence ratio image of CA1 loaded with Fura-2AM indicating location of monitored astrocytes. Four astrocytes are circled, and ratio traces over time for these astrocytes are plotted to the right in the presence of Aβ1-42, and the α7nAChR allosteric modulator PNU120596 B. Bargraph summarising astrocytic activity frequency normalised to control ACSF. C. Cumulative distribution plot of calcium event ratio amplitude for 10nM Aβ1-42 with and without the presence of PNU120596.
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pone-0081828-g002: Aβ1-42-mediated astrocytic activation is α7nAChR mediated.A. Fluorescence ratio image of CA1 loaded with Fura-2AM indicating location of monitored astrocytes. Four astrocytes are circled, and ratio traces over time for these astrocytes are plotted to the right in the presence of Aβ1-42, and the α7nAChR allosteric modulator PNU120596 B. Bargraph summarising astrocytic activity frequency normalised to control ACSF. C. Cumulative distribution plot of calcium event ratio amplitude for 10nM Aβ1-42 with and without the presence of PNU120596.

Mentions: To further investigate the mechanism and cellular action of Aβ1-42, we used the α7nAChR selective positive allosteric modulator PNU120596. Treatment with PNU120596 enhanced the response of astrocytes to Aβ1-42 (Figure 2A,B), increasing both astrocytic [Ca2+]i transient frequency (300pM: 0.054 ± 0.0098, 10nM: 0.0693 ± 0.0115, following PNU120596 300pM 0.082 ± 0.009 10nM: 0.11 ± 0.01, P<0.05, 102 astrocytes 3 preparations) (Figure 2A,B) and the ratio of the individual [Ca2+]i elevations (Figure 2C) (10nM Aβ1-42: 0.038 ± 0.0273 R, Aβ1-42 and PNU120596 0.064 ± 0.049. P<0.00001 K-S test).


α7 Nicotinic receptor-mediated astrocytic gliotransmitter release: Aβ effects in a preclinical Alzheimer's mouse model.

Pirttimaki TM, Codadu NK, Awni A, Pratik P, Nagel DA, Hill EJ, Dineley KT, Parri HR - PLoS ONE (2013)

Aβ1-42-mediated astrocytic activation is α7nAChR mediated.A. Fluorescence ratio image of CA1 loaded with Fura-2AM indicating location of monitored astrocytes. Four astrocytes are circled, and ratio traces over time for these astrocytes are plotted to the right in the presence of Aβ1-42, and the α7nAChR allosteric modulator PNU120596 B. Bargraph summarising astrocytic activity frequency normalised to control ACSF. C. Cumulative distribution plot of calcium event ratio amplitude for 10nM Aβ1-42 with and without the presence of PNU120596.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842962&req=5

pone-0081828-g002: Aβ1-42-mediated astrocytic activation is α7nAChR mediated.A. Fluorescence ratio image of CA1 loaded with Fura-2AM indicating location of monitored astrocytes. Four astrocytes are circled, and ratio traces over time for these astrocytes are plotted to the right in the presence of Aβ1-42, and the α7nAChR allosteric modulator PNU120596 B. Bargraph summarising astrocytic activity frequency normalised to control ACSF. C. Cumulative distribution plot of calcium event ratio amplitude for 10nM Aβ1-42 with and without the presence of PNU120596.
Mentions: To further investigate the mechanism and cellular action of Aβ1-42, we used the α7nAChR selective positive allosteric modulator PNU120596. Treatment with PNU120596 enhanced the response of astrocytes to Aβ1-42 (Figure 2A,B), increasing both astrocytic [Ca2+]i transient frequency (300pM: 0.054 ± 0.0098, 10nM: 0.0693 ± 0.0115, following PNU120596 300pM 0.082 ± 0.009 10nM: 0.11 ± 0.01, P<0.05, 102 astrocytes 3 preparations) (Figure 2A,B) and the ratio of the individual [Ca2+]i elevations (Figure 2C) (10nM Aβ1-42: 0.038 ± 0.0273 R, Aβ1-42 and PNU120596 0.064 ± 0.049. P<0.00001 K-S test).

Bottom Line: 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 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).

View Article: PubMed Central - PubMed

Affiliation: School of Life and Health Sciences, Aston University, Birmingham, England.

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.

Show MeSH
Related in: MedlinePlus