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Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and ?-Arrestin-1-Regulated Lactate Metabolism.

ABSTRACT: Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful.We used specific ?-adrenergic agonists, as well as ?2-adrenergic receptor (?2AR) and arrestin knockout models, to study the effects of adaptive ?2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecular and cell biological approaches to elucidate the signaling subnetworks.We observed that the duration of the adaptive ?2AR activation determines its consequences on learning and memory. Short-term formoterol treatment, for 3 to 5 days, improved cognitive function; however, prolonged ?2AR activation, for more than 6 days, produced harmful effects. We identified the activation of several signaling networks downstream of ?2AR, as well as an essential role for arrestin and lactate metabolism in promoting cognitive ability. Whereas Gs-protein kinase A-cyclic adenosine monophosphate response element binding protein signaling modulated monocarboxylate transporter 1 expression, ?-arrestin-1 controlled expression levels of monocarboxylate transporter 4 and lactate dehydrogenase A through the formation of a ?-arrestin-1/phospho-mitogen-activated protein kinase/hypoxia-inducible factor-1? ternary complex to upregulate lactate metabolism in astrocyte-derived U251 cells. Conversely, long-term treatment with formoterol led to the desensitization of ?2ARs, which was responsible for its decreased beneficial effects.Our results not only revealed that ?-arrestin-1 regulated lactate metabolism to contribute to ?2AR functions in improved memory formation, but also indicated that the appropriate management of one specific stress pathway, such as through the clinical drug formoterol, may exert beneficial effects on cognitive abilities.

SUBMITTER: Dong JH

PROVIDER: S-EPMC6088385 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1-Regulated Lactate Metabolism.

Dong Jun-Hong JH Wang Yi-Jing YJ Cui Min M Wang Xiao-Jing XJ Zheng Wen-Shuai WS Ma Ming-Liang ML Yang Fan F He Dong-Fang DF Hu Qiao-Xia QX Zhang Dao-Lai DL Ning Shang-Lei SL Liu Chun-Hua CH Wang Chuan C Wang Yue Y Li Xiang-Yao XY Yi Fan F Lin Amy A Kahsai Alem W AW Cahill Thomas Joseph TJ Chen Zhe-Yu ZY Yu Xiao X Sun Jin-Peng JP

Biological psychiatry 20161013 8

<h4>Background</h4>Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful.<h4>Methods</h4>We used specific β-adrenergic agonists, as well as β<sub>2</sub>-adrenergic receptor (β2AR) and arrestin knockout models, to study the effects of adaptive β2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecula ...[more]

PMID: 27916196

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Project description:BackgroundGene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway.MethodsHere, we generated a new mouse model with a small deletion of two key exons in Kctd13. Then, we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase, for six weeks in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region.ResultsWe found that the small Kctd13 heterozygous deletion induced a cognitive phenotype similar to the whole deletion of the 16p11.2 homologous region, in the Del/+?mice. We then showed that chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, learning and memory improvement occurred in parallel to change in the RHOA pathway.LimitationsThe Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+?model. In particular, the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18-week old mutants. Similarly, the increase in locomotor activity was not modified by the treatment in the 16p11.2 Del/+?mouse model, suggesting that other loci were involved in such defects. Rescue was observed only after four weeks of treatment but no long-term experiment has been carried out so far. Finally, we did not check the social behaviour, which requires working in another hybrid genetic background.ConclusionThese findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for 16p11.2 deletion. In addition, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.

Dataset Information

Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and ?-Arrestin-1-Regulated Lactate Metabolism.

Publications

Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1-Regulated Lactate Metabolism.

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