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Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.

Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, Guo W, Kang J, Yu GQ, Adame A, Devidze N, Dubal DB, Masliah E, Conklin BR, Mucke L - Nat. Neurosci. (2015)

Bottom Line: Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory.However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known.Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

View Article: PubMed Central - PubMed

Affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.

ABSTRACT
Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

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Conditional ablation of A2A receptors in astrocytes enhances memory in mice(a–b) GFAP-Cre/loxP-Adora2a mice were tested in the Morris water maze at 2–4 months of age. (a) Distance traveled to reach the platform during hidden platform training (two trials per session, two sessions per day for four days). Repeated measures two-way ANOVA: F(14, 308) = 0.34, P = 0.99 for interaction effect, F(2, 44) = 1.34, P = 0.27 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. (b) Probe trial conducted 6 days after training. Left: Durations in target and non-target (other) quadrants. One-way ANOVA: F(2, 42) = 3.09, P = 0.056; one-sample t-test vs. chance duration of 15 s with FDR correction for multiple comparisons (Target vs. chance): P = 0.36 (cWT), P = 0.018 (cHET), P = 0.0075 (cKO). n = 11 cWT, 18 cHET, and 16 cKO mice. #P < 0.05 vs. cWT (Dunnett’s test); *P < 0.05, **P < 0.01 (one-sample t-test). Right: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 85) = 3.66, P = 0.03 for interaction effect; F(2, 85) = 2.45, P = 0.09 for genotype effect. Student’s t-test with Welch’s correction (Target vs. Other of matching genotype): P = 0.35 (cWT), P = 0.85 (cHET), P = 0.0003 (cKO). ***P < 0.001 (Student’s t-test with Welch’s correction). (c–f) GFAPCre/loxP-Adora2a mice were tested in the open field at 2–4 months of age. (c–d) Mice were habituated to the open field in 5-min trials (1–2 trials per day) for 3 days and tested in the same arena 6 days later (day 9). (c) Repeated measures two-way ANOVA: F(12, 264) = 1.14, P = 0.33 for interaction effect, F(2, 44) = 14.99, P < 0.0001 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. #P < 0.05, ##P < 0.01, ###P < 0.001 vs. A2A-cWT (Bonferroni). Green hash tags indicate differences between A2A-cWT and A2A-cHET groups, and blue hash tags indicate differences between A2A-cWT and A2A-cKO groups. (d) Extent of dishabituation on day 9 after mice had not been tested in the same open field for 6 days (test trial 6 relative to trial 5). One-way ANOVA: F(2, 41) = 4.79, P = 0.014. n = 11 A2A-cWT, 17 A2A-cHET, and 17 A2A-cKO mice. **P < 0.01 vs. cWT (Dunnett’s test). (e–f) Mice were rehabituated to the open field in two 5-min trials in one day and tested 20 days later (day 21). (e) Repeated measures two-way ANOVA: F(6, 132) = 4.38, P = 0.0005 for interaction effect, F(2, 44) = 25.61, P < 0.0001 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. #P < 0.05, ###P < 0.001 vs. A2A-cWT (Bonferroni). (f) Extent of dishabituation on day 21 (test trial 3 relative to trial 2). One-way ANOVA: F(2, 42) = 8.27, P = 0.0009. n = 11 cWT, 17 cHET, and 17 cKO mice. *P < 0.05, **P < 0.01 vs. cWT (Dunnett’s test). (g–h) GFAP-Cre/loxP-Adora2a mice were tested in the Morris water maze at 15–17 months of age. (g) Distance traveled to reach the platform during hidden platform training (two trials per session, two sessions per day for four days). Repeated measures two-way ANOVA: F(14, 217) = 0.60, P = 0.86 for interaction effect, F(2, 31) = 1.80, P = 0.18 for genotype effect. n = 7 A2A-cWT, 15 A2A-cHET, and 11 A2A-cKO mice. (h) Probe trial conducted 6 days after training. Left: Durations in target and non-target (other) quadrants. One-way ANOVA: F(2, 30) = 4.36, P = 0.022; one-sample t-test vs. chance duration of 15 s with FDR correction for multiple comparisons (Target vs. chance): P = 0.73 (cWT), P = 0.011 (cHET), P = 0.011 (cKO). n = 7 A2A-cWT, 15 A2A-cHET, and 11 A2A-cKO mice. *P < 0.05 (one-sample t-test).#P < 0.05 vs. cWT (Dunnett’s test). Right: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 59) = 1.75, P = 0.18 for interaction effect, F(2, 59) = 0.49, P = 0.61 for genotype effect. Student’s t-test with Welch’s correction (Target vs. Other of matching genotype): P = 0.87 (cWT), P = 0.66 (cHET), P = 0.037 (cKO). *P < 0.05 (Student’s t-test with Welch’s correction). Values are means ± s.e.m.
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Figure 2: Conditional ablation of A2A receptors in astrocytes enhances memory in mice(a–b) GFAP-Cre/loxP-Adora2a mice were tested in the Morris water maze at 2–4 months of age. (a) Distance traveled to reach the platform during hidden platform training (two trials per session, two sessions per day for four days). Repeated measures two-way ANOVA: F(14, 308) = 0.34, P = 0.99 for interaction effect, F(2, 44) = 1.34, P = 0.27 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. (b) Probe trial conducted 6 days after training. Left: Durations in target and non-target (other) quadrants. One-way ANOVA: F(2, 42) = 3.09, P = 0.056; one-sample t-test vs. chance duration of 15 s with FDR correction for multiple comparisons (Target vs. chance): P = 0.36 (cWT), P = 0.018 (cHET), P = 0.0075 (cKO). n = 11 cWT, 18 cHET, and 16 cKO mice. #P < 0.05 vs. cWT (Dunnett’s test); *P < 0.05, **P < 0.01 (one-sample t-test). Right: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 85) = 3.66, P = 0.03 for interaction effect; F(2, 85) = 2.45, P = 0.09 for genotype effect. Student’s t-test with Welch’s correction (Target vs. Other of matching genotype): P = 0.35 (cWT), P = 0.85 (cHET), P = 0.0003 (cKO). ***P < 0.001 (Student’s t-test with Welch’s correction). (c–f) GFAPCre/loxP-Adora2a mice were tested in the open field at 2–4 months of age. (c–d) Mice were habituated to the open field in 5-min trials (1–2 trials per day) for 3 days and tested in the same arena 6 days later (day 9). (c) Repeated measures two-way ANOVA: F(12, 264) = 1.14, P = 0.33 for interaction effect, F(2, 44) = 14.99, P < 0.0001 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. #P < 0.05, ##P < 0.01, ###P < 0.001 vs. A2A-cWT (Bonferroni). Green hash tags indicate differences between A2A-cWT and A2A-cHET groups, and blue hash tags indicate differences between A2A-cWT and A2A-cKO groups. (d) Extent of dishabituation on day 9 after mice had not been tested in the same open field for 6 days (test trial 6 relative to trial 5). One-way ANOVA: F(2, 41) = 4.79, P = 0.014. n = 11 A2A-cWT, 17 A2A-cHET, and 17 A2A-cKO mice. **P < 0.01 vs. cWT (Dunnett’s test). (e–f) Mice were rehabituated to the open field in two 5-min trials in one day and tested 20 days later (day 21). (e) Repeated measures two-way ANOVA: F(6, 132) = 4.38, P = 0.0005 for interaction effect, F(2, 44) = 25.61, P < 0.0001 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. #P < 0.05, ###P < 0.001 vs. A2A-cWT (Bonferroni). (f) Extent of dishabituation on day 21 (test trial 3 relative to trial 2). One-way ANOVA: F(2, 42) = 8.27, P = 0.0009. n = 11 cWT, 17 cHET, and 17 cKO mice. *P < 0.05, **P < 0.01 vs. cWT (Dunnett’s test). (g–h) GFAP-Cre/loxP-Adora2a mice were tested in the Morris water maze at 15–17 months of age. (g) Distance traveled to reach the platform during hidden platform training (two trials per session, two sessions per day for four days). Repeated measures two-way ANOVA: F(14, 217) = 0.60, P = 0.86 for interaction effect, F(2, 31) = 1.80, P = 0.18 for genotype effect. n = 7 A2A-cWT, 15 A2A-cHET, and 11 A2A-cKO mice. (h) Probe trial conducted 6 days after training. Left: Durations in target and non-target (other) quadrants. One-way ANOVA: F(2, 30) = 4.36, P = 0.022; one-sample t-test vs. chance duration of 15 s with FDR correction for multiple comparisons (Target vs. chance): P = 0.73 (cWT), P = 0.011 (cHET), P = 0.011 (cKO). n = 7 A2A-cWT, 15 A2A-cHET, and 11 A2A-cKO mice. *P < 0.05 (one-sample t-test).#P < 0.05 vs. cWT (Dunnett’s test). Right: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 59) = 1.75, P = 0.18 for interaction effect, F(2, 59) = 0.49, P = 0.61 for genotype effect. Student’s t-test with Welch’s correction (Target vs. Other of matching genotype): P = 0.87 (cWT), P = 0.66 (cHET), P = 0.037 (cKO). *P < 0.05 (Student’s t-test with Welch’s correction). Values are means ± s.e.m.

Mentions: We next assessed learning and memory in 2–4-month-old A2A-cWT, A2A-cHET and A2A-cKO mice in the Morris water maze. In this test, mice learn to locate a hidden platform using spatial, extramaze cues. Specifically, the mice underwent four days of hidden platform training (two sessions per day and two trials per session). After completion of training, a probe trial was performed in which the platform was removed and putative indices of spatial memory were measured. Ablation of astrocytic A2A receptors did not affect learning during hidden platform training (Fig. 2a). However, in comparison to A2A-cWT mice, A2A-cHET and A2A-cKO mice showed enhanced memory in a probe trial conducted 6 days after training (Fig. 2b). Specifically, A2A-cHET and A2A-cKO mice showed a persistent memory for the target quadrant. A2A-cKO mice also remembered the platform location (Fig. 2b), suggesting that the ablation of astrocytic A2A receptors enhances spatial memory. Swim speeds during the probe trial were similar among the groups (Supplementary Fig. 4a).


Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.

Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, Guo W, Kang J, Yu GQ, Adame A, Devidze N, Dubal DB, Masliah E, Conklin BR, Mucke L - Nat. Neurosci. (2015)

Conditional ablation of A2A receptors in astrocytes enhances memory in mice(a–b) GFAP-Cre/loxP-Adora2a mice were tested in the Morris water maze at 2–4 months of age. (a) Distance traveled to reach the platform during hidden platform training (two trials per session, two sessions per day for four days). Repeated measures two-way ANOVA: F(14, 308) = 0.34, P = 0.99 for interaction effect, F(2, 44) = 1.34, P = 0.27 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. (b) Probe trial conducted 6 days after training. Left: Durations in target and non-target (other) quadrants. One-way ANOVA: F(2, 42) = 3.09, P = 0.056; one-sample t-test vs. chance duration of 15 s with FDR correction for multiple comparisons (Target vs. chance): P = 0.36 (cWT), P = 0.018 (cHET), P = 0.0075 (cKO). n = 11 cWT, 18 cHET, and 16 cKO mice. #P < 0.05 vs. cWT (Dunnett’s test); *P < 0.05, **P < 0.01 (one-sample t-test). Right: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 85) = 3.66, P = 0.03 for interaction effect; F(2, 85) = 2.45, P = 0.09 for genotype effect. Student’s t-test with Welch’s correction (Target vs. Other of matching genotype): P = 0.35 (cWT), P = 0.85 (cHET), P = 0.0003 (cKO). ***P < 0.001 (Student’s t-test with Welch’s correction). (c–f) GFAPCre/loxP-Adora2a mice were tested in the open field at 2–4 months of age. (c–d) Mice were habituated to the open field in 5-min trials (1–2 trials per day) for 3 days and tested in the same arena 6 days later (day 9). (c) Repeated measures two-way ANOVA: F(12, 264) = 1.14, P = 0.33 for interaction effect, F(2, 44) = 14.99, P < 0.0001 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. #P < 0.05, ##P < 0.01, ###P < 0.001 vs. A2A-cWT (Bonferroni). Green hash tags indicate differences between A2A-cWT and A2A-cHET groups, and blue hash tags indicate differences between A2A-cWT and A2A-cKO groups. (d) Extent of dishabituation on day 9 after mice had not been tested in the same open field for 6 days (test trial 6 relative to trial 5). One-way ANOVA: F(2, 41) = 4.79, P = 0.014. n = 11 A2A-cWT, 17 A2A-cHET, and 17 A2A-cKO mice. **P < 0.01 vs. cWT (Dunnett’s test). (e–f) Mice were rehabituated to the open field in two 5-min trials in one day and tested 20 days later (day 21). (e) Repeated measures two-way ANOVA: F(6, 132) = 4.38, P = 0.0005 for interaction effect, F(2, 44) = 25.61, P < 0.0001 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. #P < 0.05, ###P < 0.001 vs. A2A-cWT (Bonferroni). (f) Extent of dishabituation on day 21 (test trial 3 relative to trial 2). One-way ANOVA: F(2, 42) = 8.27, P = 0.0009. n = 11 cWT, 17 cHET, and 17 cKO mice. *P < 0.05, **P < 0.01 vs. cWT (Dunnett’s test). (g–h) GFAP-Cre/loxP-Adora2a mice were tested in the Morris water maze at 15–17 months of age. (g) Distance traveled to reach the platform during hidden platform training (two trials per session, two sessions per day for four days). Repeated measures two-way ANOVA: F(14, 217) = 0.60, P = 0.86 for interaction effect, F(2, 31) = 1.80, P = 0.18 for genotype effect. n = 7 A2A-cWT, 15 A2A-cHET, and 11 A2A-cKO mice. (h) Probe trial conducted 6 days after training. Left: Durations in target and non-target (other) quadrants. One-way ANOVA: F(2, 30) = 4.36, P = 0.022; one-sample t-test vs. chance duration of 15 s with FDR correction for multiple comparisons (Target vs. chance): P = 0.73 (cWT), P = 0.011 (cHET), P = 0.011 (cKO). n = 7 A2A-cWT, 15 A2A-cHET, and 11 A2A-cKO mice. *P < 0.05 (one-sample t-test).#P < 0.05 vs. cWT (Dunnett’s test). Right: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 59) = 1.75, P = 0.18 for interaction effect, F(2, 59) = 0.49, P = 0.61 for genotype effect. Student’s t-test with Welch’s correction (Target vs. Other of matching genotype): P = 0.87 (cWT), P = 0.66 (cHET), P = 0.037 (cKO). *P < 0.05 (Student’s t-test with Welch’s correction). Values are means ± s.e.m.
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Figure 2: Conditional ablation of A2A receptors in astrocytes enhances memory in mice(a–b) GFAP-Cre/loxP-Adora2a mice were tested in the Morris water maze at 2–4 months of age. (a) Distance traveled to reach the platform during hidden platform training (two trials per session, two sessions per day for four days). Repeated measures two-way ANOVA: F(14, 308) = 0.34, P = 0.99 for interaction effect, F(2, 44) = 1.34, P = 0.27 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. (b) Probe trial conducted 6 days after training. Left: Durations in target and non-target (other) quadrants. One-way ANOVA: F(2, 42) = 3.09, P = 0.056; one-sample t-test vs. chance duration of 15 s with FDR correction for multiple comparisons (Target vs. chance): P = 0.36 (cWT), P = 0.018 (cHET), P = 0.0075 (cKO). n = 11 cWT, 18 cHET, and 16 cKO mice. #P < 0.05 vs. cWT (Dunnett’s test); *P < 0.05, **P < 0.01 (one-sample t-test). Right: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 85) = 3.66, P = 0.03 for interaction effect; F(2, 85) = 2.45, P = 0.09 for genotype effect. Student’s t-test with Welch’s correction (Target vs. Other of matching genotype): P = 0.35 (cWT), P = 0.85 (cHET), P = 0.0003 (cKO). ***P < 0.001 (Student’s t-test with Welch’s correction). (c–f) GFAPCre/loxP-Adora2a mice were tested in the open field at 2–4 months of age. (c–d) Mice were habituated to the open field in 5-min trials (1–2 trials per day) for 3 days and tested in the same arena 6 days later (day 9). (c) Repeated measures two-way ANOVA: F(12, 264) = 1.14, P = 0.33 for interaction effect, F(2, 44) = 14.99, P < 0.0001 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. #P < 0.05, ##P < 0.01, ###P < 0.001 vs. A2A-cWT (Bonferroni). Green hash tags indicate differences between A2A-cWT and A2A-cHET groups, and blue hash tags indicate differences between A2A-cWT and A2A-cKO groups. (d) Extent of dishabituation on day 9 after mice had not been tested in the same open field for 6 days (test trial 6 relative to trial 5). One-way ANOVA: F(2, 41) = 4.79, P = 0.014. n = 11 A2A-cWT, 17 A2A-cHET, and 17 A2A-cKO mice. **P < 0.01 vs. cWT (Dunnett’s test). (e–f) Mice were rehabituated to the open field in two 5-min trials in one day and tested 20 days later (day 21). (e) Repeated measures two-way ANOVA: F(6, 132) = 4.38, P = 0.0005 for interaction effect, F(2, 44) = 25.61, P < 0.0001 for genotype effect. n = 12 A2A-cWT, 18 A2A-cHET, and 17 A2A-cKO mice. #P < 0.05, ###P < 0.001 vs. A2A-cWT (Bonferroni). (f) Extent of dishabituation on day 21 (test trial 3 relative to trial 2). One-way ANOVA: F(2, 42) = 8.27, P = 0.0009. n = 11 cWT, 17 cHET, and 17 cKO mice. *P < 0.05, **P < 0.01 vs. cWT (Dunnett’s test). (g–h) GFAP-Cre/loxP-Adora2a mice were tested in the Morris water maze at 15–17 months of age. (g) Distance traveled to reach the platform during hidden platform training (two trials per session, two sessions per day for four days). Repeated measures two-way ANOVA: F(14, 217) = 0.60, P = 0.86 for interaction effect, F(2, 31) = 1.80, P = 0.18 for genotype effect. n = 7 A2A-cWT, 15 A2A-cHET, and 11 A2A-cKO mice. (h) Probe trial conducted 6 days after training. Left: Durations in target and non-target (other) quadrants. One-way ANOVA: F(2, 30) = 4.36, P = 0.022; one-sample t-test vs. chance duration of 15 s with FDR correction for multiple comparisons (Target vs. chance): P = 0.73 (cWT), P = 0.011 (cHET), P = 0.011 (cKO). n = 7 A2A-cWT, 15 A2A-cHET, and 11 A2A-cKO mice. *P < 0.05 (one-sample t-test).#P < 0.05 vs. cWT (Dunnett’s test). Right: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 59) = 1.75, P = 0.18 for interaction effect, F(2, 59) = 0.49, P = 0.61 for genotype effect. Student’s t-test with Welch’s correction (Target vs. Other of matching genotype): P = 0.87 (cWT), P = 0.66 (cHET), P = 0.037 (cKO). *P < 0.05 (Student’s t-test with Welch’s correction). Values are means ± s.e.m.
Mentions: We next assessed learning and memory in 2–4-month-old A2A-cWT, A2A-cHET and A2A-cKO mice in the Morris water maze. In this test, mice learn to locate a hidden platform using spatial, extramaze cues. Specifically, the mice underwent four days of hidden platform training (two sessions per day and two trials per session). After completion of training, a probe trial was performed in which the platform was removed and putative indices of spatial memory were measured. Ablation of astrocytic A2A receptors did not affect learning during hidden platform training (Fig. 2a). However, in comparison to A2A-cWT mice, A2A-cHET and A2A-cKO mice showed enhanced memory in a probe trial conducted 6 days after training (Fig. 2b). Specifically, A2A-cHET and A2A-cKO mice showed a persistent memory for the target quadrant. A2A-cKO mice also remembered the platform location (Fig. 2b), suggesting that the ablation of astrocytic A2A receptors enhances spatial memory. Swim speeds during the probe trial were similar among the groups (Supplementary Fig. 4a).

Bottom Line: Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory.However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known.Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

View Article: PubMed Central - PubMed

Affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.

ABSTRACT
Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

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Related in: MedlinePlus