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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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Rs1 ligand impairs memory in GFAP-Rs1 miceGFAP-tTA (Con) and GFAP-Rs1 mice were tested in the Morris water maze at 2–11 months of age. (a) Experimental design for data in (b and c). On two consecutive days, mice were injected with saline or the Rs1 ligand GR-125487 (GR, 3 mg/kg/day, i.p.) 15 min before hidden platform training. Memory of the platform location was tested in a probe trial (platform removed) two days after completing training. (b) Distance traveled to reach the platform during training. Two-way ANOVA: F(9, 273) = 0.34, P = 0.96 for interaction effect. n = 27 Con/Saline, 29 Con/GR, 19 GFAP-Rs1/Saline, and 20 GFAP-Rs1/GR mice. (c) Probe. Left: Crossings of target and equivalent non-target (other) locations. Two-way ANOVA: F(1, 89) = 4.15, P = 0.045 for genotype by treatment interaction. Student’s t-test with Welch’s correction (Target vs. Other): P < 0.0001 (Con/Saline), P < 0.0001 (Con/GR), P = 0.0001 (GFAP-Rs1/Saline), P = 0.027 (GFAPRs1/GR). ***P < 0.001, *P < 0.05 (Student’s t-test with Welch’s correction). Right: Latency to reach target location. Two-way ANOVA: F(1, 89) = 8.56, P = 0.0044 for interaction effect. n = 27 Con/Saline, 28 Con/GR, 18 GFAP-Rs1/Saline, and 20 GFAP-Rs1/GR mice. (d) Experimental design for data in (e and f). Mice previously treated with GR and tested as in (a) were injected i.p. with saline 15 min before retraining to a new hidden platform location in a new context. Memory was tested in a probe three days after completing retraining. (e) Distance traveled to reach the platform during retraining. Two-way ANOVA: F(3, 75) = 0.72, P = 0.54 for interaction effect. n = 15 Con/Saline and 12 GFAP-Rs1/Saline mice. (f) Probe. Left: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(1, 49) = 1.08, P = 0.31 for interaction effect. Student’s t-test with Welch’s correction (Target vs. Other): P = 0.0007 (Con/Saline), P = 0.0097 (GFAP-Rs1/Saline). Right: Latency to reach target location (P = 0.35, one-tailed Student’s t-test). n = 15 Con/Saline and 12 GFAP-Rs1/Saline mice. (g) Experimental design for data in (h and i). An independent cohort of mice was injected with saline or GR one day after completing hidden platform training and probe tested the following day. (h) Distance traveled to reach the platform during training. Two-way ANOVA: F(5, 99) = 0.31, P = 0.91 for interaction effect. n = 20 Con/Saline, 20 Con/GR, 16 GFAP-Rs1/Saline, and 16 GFAP-Rs1/GR mice. (i) Probe. Left: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 96) = 1.17, P = 0.31 for interaction effect. Student’s t-test with Welch’s correction (Target vs. Other): P = 0.001 (Con/Saline), P = 0.005 (Con/GR), P = 0.019 (GFAP-Rs1/Saline), P = 0.965 (GFAP-Rs1/GR). Right: Latency to reach target location. Two-way ANOVA: F(2, 94) = 3.08, P = 0.0507 for interaction effect. n = 19 Con/Saline, 18 Con/GR, 16 GFAP-Rs1/Saline, and 16 GFAP-Rs1/GR mice. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t-test with Welch’s correction); #P < 0.05, ##P < 0.01 vs. GR-treated Con or saline-treated GFAP-Rs1 (Bonferroni test). Values are means ± s.e.m.
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Figure 5: Rs1 ligand impairs memory in GFAP-Rs1 miceGFAP-tTA (Con) and GFAP-Rs1 mice were tested in the Morris water maze at 2–11 months of age. (a) Experimental design for data in (b and c). On two consecutive days, mice were injected with saline or the Rs1 ligand GR-125487 (GR, 3 mg/kg/day, i.p.) 15 min before hidden platform training. Memory of the platform location was tested in a probe trial (platform removed) two days after completing training. (b) Distance traveled to reach the platform during training. Two-way ANOVA: F(9, 273) = 0.34, P = 0.96 for interaction effect. n = 27 Con/Saline, 29 Con/GR, 19 GFAP-Rs1/Saline, and 20 GFAP-Rs1/GR mice. (c) Probe. Left: Crossings of target and equivalent non-target (other) locations. Two-way ANOVA: F(1, 89) = 4.15, P = 0.045 for genotype by treatment interaction. Student’s t-test with Welch’s correction (Target vs. Other): P < 0.0001 (Con/Saline), P < 0.0001 (Con/GR), P = 0.0001 (GFAP-Rs1/Saline), P = 0.027 (GFAPRs1/GR). ***P < 0.001, *P < 0.05 (Student’s t-test with Welch’s correction). Right: Latency to reach target location. Two-way ANOVA: F(1, 89) = 8.56, P = 0.0044 for interaction effect. n = 27 Con/Saline, 28 Con/GR, 18 GFAP-Rs1/Saline, and 20 GFAP-Rs1/GR mice. (d) Experimental design for data in (e and f). Mice previously treated with GR and tested as in (a) were injected i.p. with saline 15 min before retraining to a new hidden platform location in a new context. Memory was tested in a probe three days after completing retraining. (e) Distance traveled to reach the platform during retraining. Two-way ANOVA: F(3, 75) = 0.72, P = 0.54 for interaction effect. n = 15 Con/Saline and 12 GFAP-Rs1/Saline mice. (f) Probe. Left: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(1, 49) = 1.08, P = 0.31 for interaction effect. Student’s t-test with Welch’s correction (Target vs. Other): P = 0.0007 (Con/Saline), P = 0.0097 (GFAP-Rs1/Saline). Right: Latency to reach target location (P = 0.35, one-tailed Student’s t-test). n = 15 Con/Saline and 12 GFAP-Rs1/Saline mice. (g) Experimental design for data in (h and i). An independent cohort of mice was injected with saline or GR one day after completing hidden platform training and probe tested the following day. (h) Distance traveled to reach the platform during training. Two-way ANOVA: F(5, 99) = 0.31, P = 0.91 for interaction effect. n = 20 Con/Saline, 20 Con/GR, 16 GFAP-Rs1/Saline, and 16 GFAP-Rs1/GR mice. (i) Probe. Left: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 96) = 1.17, P = 0.31 for interaction effect. Student’s t-test with Welch’s correction (Target vs. Other): P = 0.001 (Con/Saline), P = 0.005 (Con/GR), P = 0.019 (GFAP-Rs1/Saline), P = 0.965 (GFAP-Rs1/GR). Right: Latency to reach target location. Two-way ANOVA: F(2, 94) = 3.08, P = 0.0507 for interaction effect. n = 19 Con/Saline, 18 Con/GR, 16 GFAP-Rs1/Saline, and 16 GFAP-Rs1/GR mice. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t-test with Welch’s correction); #P < 0.05, ##P < 0.01 vs. GR-treated Con or saline-treated GFAP-Rs1 (Bonferroni test). Values are means ± s.e.m.

Mentions: The relatively rapid brain entry and clearance of the Rs1 ligand made it possible to test the effects of astrocytic Gs-coupled signaling on different stages of spatial learning and memory in the Morris water maze. The doubly transgenic GFAP-Rs1 mice and their littermate controls were generated on an F1 hybrid background consisting of 50% C57BL/6J and 50% FVB/N. Such hybrid mice perform better in the Morris water maze than congenic C57BL/6J mice.34 Therefore, the hybrid mice underwent only two days of hidden platform training in the Morris water maze (two sessions per day and two trials per session) before testing in probe trials. On each day of training, mice received a single injection of GR-125487 (3 mg/kg, i.p.) or saline 15 min before training (Fig. 5a). The daily training took 30 min or less to complete, coincident with peak brain ligand concentrations (Fig. 4f). Two days after completion of training, one probe trial was performed.


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)

Rs1 ligand impairs memory in GFAP-Rs1 miceGFAP-tTA (Con) and GFAP-Rs1 mice were tested in the Morris water maze at 2–11 months of age. (a) Experimental design for data in (b and c). On two consecutive days, mice were injected with saline or the Rs1 ligand GR-125487 (GR, 3 mg/kg/day, i.p.) 15 min before hidden platform training. Memory of the platform location was tested in a probe trial (platform removed) two days after completing training. (b) Distance traveled to reach the platform during training. Two-way ANOVA: F(9, 273) = 0.34, P = 0.96 for interaction effect. n = 27 Con/Saline, 29 Con/GR, 19 GFAP-Rs1/Saline, and 20 GFAP-Rs1/GR mice. (c) Probe. Left: Crossings of target and equivalent non-target (other) locations. Two-way ANOVA: F(1, 89) = 4.15, P = 0.045 for genotype by treatment interaction. Student’s t-test with Welch’s correction (Target vs. Other): P < 0.0001 (Con/Saline), P < 0.0001 (Con/GR), P = 0.0001 (GFAP-Rs1/Saline), P = 0.027 (GFAPRs1/GR). ***P < 0.001, *P < 0.05 (Student’s t-test with Welch’s correction). Right: Latency to reach target location. Two-way ANOVA: F(1, 89) = 8.56, P = 0.0044 for interaction effect. n = 27 Con/Saline, 28 Con/GR, 18 GFAP-Rs1/Saline, and 20 GFAP-Rs1/GR mice. (d) Experimental design for data in (e and f). Mice previously treated with GR and tested as in (a) were injected i.p. with saline 15 min before retraining to a new hidden platform location in a new context. Memory was tested in a probe three days after completing retraining. (e) Distance traveled to reach the platform during retraining. Two-way ANOVA: F(3, 75) = 0.72, P = 0.54 for interaction effect. n = 15 Con/Saline and 12 GFAP-Rs1/Saline mice. (f) Probe. Left: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(1, 49) = 1.08, P = 0.31 for interaction effect. Student’s t-test with Welch’s correction (Target vs. Other): P = 0.0007 (Con/Saline), P = 0.0097 (GFAP-Rs1/Saline). Right: Latency to reach target location (P = 0.35, one-tailed Student’s t-test). n = 15 Con/Saline and 12 GFAP-Rs1/Saline mice. (g) Experimental design for data in (h and i). An independent cohort of mice was injected with saline or GR one day after completing hidden platform training and probe tested the following day. (h) Distance traveled to reach the platform during training. Two-way ANOVA: F(5, 99) = 0.31, P = 0.91 for interaction effect. n = 20 Con/Saline, 20 Con/GR, 16 GFAP-Rs1/Saline, and 16 GFAP-Rs1/GR mice. (i) Probe. Left: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 96) = 1.17, P = 0.31 for interaction effect. Student’s t-test with Welch’s correction (Target vs. Other): P = 0.001 (Con/Saline), P = 0.005 (Con/GR), P = 0.019 (GFAP-Rs1/Saline), P = 0.965 (GFAP-Rs1/GR). Right: Latency to reach target location. Two-way ANOVA: F(2, 94) = 3.08, P = 0.0507 for interaction effect. n = 19 Con/Saline, 18 Con/GR, 16 GFAP-Rs1/Saline, and 16 GFAP-Rs1/GR mice. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t-test with Welch’s correction); #P < 0.05, ##P < 0.01 vs. GR-treated Con or saline-treated GFAP-Rs1 (Bonferroni test). Values are means ± s.e.m.
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Figure 5: Rs1 ligand impairs memory in GFAP-Rs1 miceGFAP-tTA (Con) and GFAP-Rs1 mice were tested in the Morris water maze at 2–11 months of age. (a) Experimental design for data in (b and c). On two consecutive days, mice were injected with saline or the Rs1 ligand GR-125487 (GR, 3 mg/kg/day, i.p.) 15 min before hidden platform training. Memory of the platform location was tested in a probe trial (platform removed) two days after completing training. (b) Distance traveled to reach the platform during training. Two-way ANOVA: F(9, 273) = 0.34, P = 0.96 for interaction effect. n = 27 Con/Saline, 29 Con/GR, 19 GFAP-Rs1/Saline, and 20 GFAP-Rs1/GR mice. (c) Probe. Left: Crossings of target and equivalent non-target (other) locations. Two-way ANOVA: F(1, 89) = 4.15, P = 0.045 for genotype by treatment interaction. Student’s t-test with Welch’s correction (Target vs. Other): P < 0.0001 (Con/Saline), P < 0.0001 (Con/GR), P = 0.0001 (GFAP-Rs1/Saline), P = 0.027 (GFAPRs1/GR). ***P < 0.001, *P < 0.05 (Student’s t-test with Welch’s correction). Right: Latency to reach target location. Two-way ANOVA: F(1, 89) = 8.56, P = 0.0044 for interaction effect. n = 27 Con/Saline, 28 Con/GR, 18 GFAP-Rs1/Saline, and 20 GFAP-Rs1/GR mice. (d) Experimental design for data in (e and f). Mice previously treated with GR and tested as in (a) were injected i.p. with saline 15 min before retraining to a new hidden platform location in a new context. Memory was tested in a probe three days after completing retraining. (e) Distance traveled to reach the platform during retraining. Two-way ANOVA: F(3, 75) = 0.72, P = 0.54 for interaction effect. n = 15 Con/Saline and 12 GFAP-Rs1/Saline mice. (f) Probe. Left: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(1, 49) = 1.08, P = 0.31 for interaction effect. Student’s t-test with Welch’s correction (Target vs. Other): P = 0.0007 (Con/Saline), P = 0.0097 (GFAP-Rs1/Saline). Right: Latency to reach target location (P = 0.35, one-tailed Student’s t-test). n = 15 Con/Saline and 12 GFAP-Rs1/Saline mice. (g) Experimental design for data in (h and i). An independent cohort of mice was injected with saline or GR one day after completing hidden platform training and probe tested the following day. (h) Distance traveled to reach the platform during training. Two-way ANOVA: F(5, 99) = 0.31, P = 0.91 for interaction effect. n = 20 Con/Saline, 20 Con/GR, 16 GFAP-Rs1/Saline, and 16 GFAP-Rs1/GR mice. (i) Probe. Left: Crossings of target and non-target (other) platform locations. Two-way ANOVA: F(2, 96) = 1.17, P = 0.31 for interaction effect. Student’s t-test with Welch’s correction (Target vs. Other): P = 0.001 (Con/Saline), P = 0.005 (Con/GR), P = 0.019 (GFAP-Rs1/Saline), P = 0.965 (GFAP-Rs1/GR). Right: Latency to reach target location. Two-way ANOVA: F(2, 94) = 3.08, P = 0.0507 for interaction effect. n = 19 Con/Saline, 18 Con/GR, 16 GFAP-Rs1/Saline, and 16 GFAP-Rs1/GR mice. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t-test with Welch’s correction); #P < 0.05, ##P < 0.01 vs. GR-treated Con or saline-treated GFAP-Rs1 (Bonferroni test). Values are means ± s.e.m.
Mentions: The relatively rapid brain entry and clearance of the Rs1 ligand made it possible to test the effects of astrocytic Gs-coupled signaling on different stages of spatial learning and memory in the Morris water maze. The doubly transgenic GFAP-Rs1 mice and their littermate controls were generated on an F1 hybrid background consisting of 50% C57BL/6J and 50% FVB/N. Such hybrid mice perform better in the Morris water maze than congenic C57BL/6J mice.34 Therefore, the hybrid mice underwent only two days of hidden platform training in the Morris water maze (two sessions per day and two trials per session) before testing in probe trials. On each day of training, mice received a single injection of GR-125487 (3 mg/kg, i.p.) or saline 15 min before training (Fig. 5a). The daily training took 30 min or less to complete, coincident with peak brain ligand concentrations (Fig. 4f). Two days after completion of training, one probe trial was performed.

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