Long-term α1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity

Abstract

The role of α(1)-adrenergic receptors (α(1)ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. α(1A)AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term α(1A)AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the α(1A)AR. CAM-α(1A)AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the α(1A)AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-α(1A)AR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the α(1A)AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-α(1A)AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-α(1A)AR mice was 10% longer than that of WT mice. Our results suggest that long-term α(1A)AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders.

Fig. 1.

Long-term α_1AAR stimulation improves cognitive performance in the Barnes maze. During learning trials, CAM-α_1AAR mice (n = 17) took less time to solve the maze (A₁) and made fewer errors (A₂) compared with the WT mice (n = 15). During memory trials, CAM-α_1AAR mice took less time to solve the maze (B₁) and made fewer errors (B₂) compared with WT mice. Schematic drawings represent paths traveled during learning (C₁) and memory (C₂) trials of the WT and CAM-α_1AAR mice. The bar graph insets show the mean solve time and errors during learning and memory trials. Statistically significant at *, p < 0.05; **, p < 0.01; or ***, p < 0.001.

Fig. 2.

Learning and memory in the Morris water maze is enhanced with long-term α_1AAR activation. A, CAM-α_1AAR mice (n = 11) took less time than the WT mice (n = 11) to reach the correct platform on day 1 of the learning phase. B, when the platform and spatial clues were reversed on day 9 to test memory, CAM-α_1AAR mice completed the maze in less time than WT mice. Statistically significant at *, p < 0.05.

Fig. 3.

Long-term α_1AAR stimulation increases spatial working memory in the multi-T maze. Schematic diagram of Multi-T maze (A₁). During the learning phase, CAM-α_1AAR mice (n = 9) took less time to solve the maze (A₂) and made fewer errors (A₃) than the WT mice (n = 11). During memory trials, CAM-α_1AAR mice took less time to solve (B₁) and made fewer errors (B₂) than the WT mice. The bar graph insets show the mean solve time and errors during memory testing. Statistically significant at **, p < 0.01 or ***, p < 0.001.

Fig. 4.

Hippocampal synaptic plasticity is enhanced with long-term α_1AAR activation. A, basal synaptic transmission, as determined by the input-output relation between fiber volley amplitude and fEPSP slope, is increased in CAM-α_1AAR (n = 11 slices from three animals) compared with WT mice (n = 23 slices from seven animals). The bar graph inset shows the mean input-output slopes. B, frequency facilitation (PPF) is enhanced in the CAM-α_1AAR mice (n = 21 slices from three animals) compared with the WT mice (n = 23 slices from seven animals). The facilitation was plotted as a function of interpulse interval of 35, 50, 75, 100, 150, 200, and 300 ms. Superimposed representative fEPSPs were recorded at 150 ms interval. C₁, long-term α_1AAR activation enhances LTP in the hippocampal CA1 region, shown by cumulative data of the normalized changes in field potential slope in CAM-α_1AAR mice (n = 23 slices from nine animals) and WT mice (n = 27 slices from nine animals). Superimposed representative fEPSPs were recorded 15 min before and 60 min after LTP induction. C₂, multiple LTP recordings for each mouse were grouped and averaged, giving a single fEPSP slope ratio per animal at different time points before or after TBS (−15, 15, 30, and 60 min). CAM-α_1AAR mice (n = 9) showed enhanced mean LTP compared with WT mice (n = 9) at each post-TBS time point. Statistically significant at *, p < 0.05; *, p < 0.01; or ***, p < 0.001.

Fig. 5.

Long-term treatment with an α_1AAR-selective agonist improves cognitive function. Normal WT mice treated for 9 months with the α_1AAR-selective agonist cirazoline (n = 11) solved the Barnes maze in less time (A₁) and made fewer errors (A₂) than the control WT mice (n = 14) on the last day (day 4) of learning trials. Likewise, WT mice treated with cirazoline for 2 months (n = 10) solved the multi-T maze in less time (B₁) and made fewer errors (B₂) than the control WT mice (n = 11) on the last day (day 5) of learning trials. During memory trials, cirazoline-treated WT mice exhibited took less time to solve (C₁ and D₁) and made fewer errors (C₂ and D₂) than the control WT mice in both the Barnes and multi-T mazes. The bar graph insets show the mean solve time and errors during memory testing. Statistically significant at *, p < 0.05 or **, p < 0.01.

Fig. 6.

Cognitive performance in the Barnes maze is reduced in mice lacking α_1AARs. During learning trials, α_1AAR-KO mice (n = 12) took more time to solve the maze (A₁) and made more errors (A₂) compared with the WT mice (n = 10). During memory trials, α_1AAR-KO mice took more time to solve the maze (B₁) and made more errors (B₂) compared with WT mice. Schematic drawings represent paths traveled during learning (C₁) and memory (C₂) trials of the WT and α_1AAR-KO mice. The bar graph insets show the mean solve time and errors during learning and memory trials. Statistically significant at *, p < 0.05.

Fig. 7.

Long-term α_1AAR stimulation does not alter locomotor activity. An open field locomotion test revealed no difference in locomotor activity between the CAM-α_1AAR (n = 12) and WT mice (n = 7).

Fig. 8.

Long-term α_1AAR activation improves mood. Rodent tests of anxiety and depression show that α_1AAR stimulation increases antidepressant-like behavior and decreases anxiety-related behaviors in mice. A, α_1AAR activation elicits antidepressant-like behaviors in the tail-suspension test. CAM-α_1AAR mice (n = 19) spent less time immobile than the WT mice (n = 33). B, α_1AAR stimulation reduces obsessive-compulsive type anxiety in the marble-burying test. CAM-α_1AAR mice (n = 21) buried fewer marbles than WT mice (n = 36). α_1AAR activation decreases anxiety-like behaviors in the elevated zero maze, as CAM-α_1AAR mice (n = 20) spent more time in (C₁) and made more entries into (C₂) the open areas than WT mice (n = 36). α_1AAR stimulation also reduces anxiety-like behaviors in the light/dark exploration. CAM-α_1AAR mice (n = 21) spent more time in the light side of the box (D₁) and made more transitions to the dark side (D₂) than WT mice (n = 34). Statistically significant at **, p < 0.01 or ***, p < 0.001.

Fig. 9.

Long-term α_1AAR stimulation improves murine longevity. Kaplan-Meier survival plots of the CAM-α_1AAR (n = 32) and WT (n = 54) mice show that α_1AAR stimulation extends the average murine lifespan. p values were calculated using the Mantel-Cox log-rank test, and each symbol represents one mouse. CAM-α_1AAR mice had an increased lifespan compared with the WT mice (χ² = 7.2; df 1; p < 0.01). See also Table 1.