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Up-regulation of mTOR signaling pathway in forebrain neurons leads to improvement of cognitive functions in pten knock-out mice

100%

Chwin N., Kiryk A., Zglinicki B., Konopka W.

Acta Neurobiologiae Experimentalis

2017

tom 77

nr Suppl.1

INTRODUCTION: PI3K-Akt-mTOR pathway plays important role in long-term synaptic plasticity and memory formation. In our studies describing the Dicer1 gene knock-out model we have shown that improved learning and memory phenotype in these mice was related to up-regulation of the PI3K-Akt-mTOR pathway. In order to prove that the PI3K-Akt-mTOR pathway is crucial for observed phenotype we have generated Pten gene knock-out model in which this up-regulation is achieved by elevation of intracellular levels of phosphatidylinositide 3 in neurons. To examine cognitive functions in Pten model, we have used the IntelliCage system. AIM(S): The puropse of our research was to define the cognitive functions in Pten/CaMKCreERT2 mouse model. METHOD(S): Mouse model: We used Pten/CaMKCreERT2 mouse model in which up-regulation of mTOR activity was generated by mutation of Pten gene restricted to forebrain neurons induced by tamoxifen. Behavioral tests: Following induction of the mutation, Pten mutant mice and controls were tested in learning and memory test in the IntelliCage: a fully automated system for the behavioral assessment of mice that live in social groups. We measured spatial learning with appetitive reinforcement in place preference learning task. RESULTS: Life span: Long-term of PI3K-Akt-mTOR pathway activity in the brain led to increased mutant mice mortality. Pten mutants were able to survive no longer than 13 weeks after the induction of mutation. Place learning in IntelliCage: In the IntelliCage, housing and testing occur in the same cage that is a familiar environment, thus creating a unique opportunity to test behavior for a long-term period in relatively low-stress conditions without handling or social isolation. Using the system, we were able to discover the better performance of Pten mutants in place learning task. Moreover, improved memory was detectable even 24 hours before the death. CONCLUSIONS: Pten/CaMKCreERT2 mice show enhanced memory of rewarded place compare to control littermates. In mutants show decreased life span.

Up-regulation of PI3K‑Akt‑mTOR signaling pathway in neurons affects cognitive functions and social interactions in a mouse model

88%

Chwin N., Kiryk A., Bijoch L., Hamed A., Konopka W.

Acta Neurobiologiae Experimentalis

2019

tom 79

nr Suppl.1

INTRODUCTION: The PI3K-Akt-mTOR pathway plays an important role in neuronal plasticity. In normal conditions, activity of this pathway is controlled by Pten phosphatase. AIM(S): We showed that loss of Pten gene in neurons evoked long-term up-regulation of PI3K-Akt-mTOR and temporarily improved learning and memory in mouse models. Moreover, we observed changes in mice vocalization during social interaction and in cellular physiology during electrophysiological recordings. METHOD(S): Mice model: Inactivation of Pten gene was investigated in 2 models: Pten/CaMKCreERT2, and Pten‑flox injected by AAV vectors. The mutation was restricted to forebrain and hippocampal neurons, respectively. Behavioral testing: Both models and respective controls were tested in a learning and memory test in IntelliCage. We measured spatial learning with appetitive behaviors. We also measured the ability to associate an aversive stimulus in the Contextual Fear Conditioning and social interaction in the Three Chamber Sociability and Social Novelty. Life span: Long‑term activity of the PI3K-Akt-mTOR pathway led to increased mortality of Pten/CaMKCreERT2 mutants. RESULTS: IntelliCage: We discovered better performance of Pten/CaMKCreERT2 mutants in the PL task. The memory improvement lasted to even 24 hours before the death. FC task: Mice developed stronger aversive memory than controls, manifested as increased freezing behavior. Both mutant models showed improved cognitive functions, and Pten/CaMKCreERT2 mice showed a decrease life span. CONCLUSIONS: Pten-flox-AAV mice developed enhanced contextual fear memory before neurodegeneration in hippocampus occurred and Pten-flox-AAV mice had intensified vocalizations with disturbed sound architecture in social interactions.

Ograniczanie wyników

2 Acta Neurobiologiae Experimentalis

2 Chwin N.

2 Kiryk A.

2 Konopka W.

1 Bijoch L.

1 Hamed A.

1 Zglinicki B.

1 2019

1 2017

Wyniki wyszukiwania

Up-regulation of mTOR signaling pathway in forebrain neurons leads to improvement of cognitive functions in pten knock-out mice

Up-regulation of PI3K‑Akt‑mTOR signaling pathway in neurons affects cognitive functions and social interactions in a mouse model