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Phenotypic rescue via mTOR inhibition in neuron-specific Pten knockout mice reveals AKT and mTORC1-site specific changes

Molecular Psychiatry volume 30, pages 3077–3089 (2025) Cite this article

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Abstract

Phosphatase and Tensin Homolog (PTEN) is a dual-specific protein and lipid phosphatase that regulates AKT and downstream signaling of the mechanistic target of rapamycin (mTOR). PTEN functions as a tumor suppressor gene whose mutations result in PTEN Hamartoma Tumor Syndrome (PHTS) characterized by increased cancer risk and neurodevelopmental comorbidity. Here, we generated a novel neuron-specific Pten knock-out mouse model (Syn-Cre/Pten HOM) to test the ability of pharmacologic mTOR inhibition to rescue Pten mutation-associated disease phenotypes in vivo and in vitro. We found that treatment with the mTOR inhibitor, everolimus, increased the survival of Syn-Cre/Pten HOM mice while some neurologic phenotypes persisted. Transcriptomic analyses revealed that in contrast to mice harboring a neuron-specific deletion of the Tuberous Sclerosis Complex 2 gene (Syn-Cre/Tsc2 KO), genes that are under AKT regulation were significantly increased in the Syn-Cre/Pten HOM mice. In addition, genes associated with synapse, extracellular matrix, and myelination were broadly increased in Syn-Cre/Pten HOM mouse neocortex. These findings were confirmed by immunostaining of cortical sections in vivo, which revealed excessive immunoreactivity of myelin basic protein and perineuronal nets (PNN), the specialized extracellular matrix surrounding fast-spiking parvalbumin (PV) interneurons. We also detected increased expression of Synapsin I/PSD95 positive synapses and network hyperactivity phenotypes in Syn-Cre/Pten HOM mice neurons compared to wild-type (WT) neurons in vitro. Strikingly, everolimus treatment rescued the number of synapses and network hyperactivity in the Syn-Cre/Pten HOM mice cortical neuron cultures. Taken together, our results revealed in vivo and in vitro molecular and neuronal network mechanisms underlying neurological phenotypes of PHTS. Notably, pharmacologic mTOR inhibition by everolimus led to successful downstream signaling rescue, including mTOR complex 1 (mTORC1) site-specific suppression of S6 phosphorylation, correlating with phenotypic rescue found in our novel neuron-specific Syn-Cre/Pten HOM mice.

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Fig. 1: Somatic development and survival of Syn-Cre/Pten mutant mice.
The alternative text for this image may have been generated using AI.
Fig. 2: Western blot analysis of mTOR-related signaling in Syn-Cre/Pten mutant mouse cortex.
The alternative text for this image may have been generated using AI.
Fig. 3: RNA Sequencing and Data Analysis of Syn-Cre/Pten- and Syn-Cre/TSC2-mutant mouse cortex.
The alternative text for this image may have been generated using AI.
Fig. 4: Immunofluorescence analysis of phospho-S6, myelin basic protein (MBP), parvalbumin (PV), and perineuronal nets (PNN) in Syn-Cre/Pten mutant mouse neocortex.
The alternative text for this image may have been generated using AI.
Fig. 5: Synaptic puncta expression and neuronal network activities in the Syn-Cre/Pten HOM cortical neurons.
The alternative text for this image may have been generated using AI.

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Data availability

RNAseq data are available at GEO with accession number GSE288965. The other data are available upon reasonable request to the corresponding author.

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Acknowledgements

We would like to thank the members of Sahin Laboratory and Rotenberg Laboratory for their assistance in this project and critical comments, as well as the Cellular Imaging Core (Dr. Harry Cramer) and the Experimental Neurophysiology Core (Sameer Dhamne) of the Intellectual and Developmental Disabilities Research Center (IDDRC) for the assistance in this project (funded by NIH/NICHD P50 HD105351).

Funding

This work has been funded, in part, by the PTEN Research Foundation, a charity governed by English law (charity number 117358), awarded to Prof. Mustafa Sahin under grant number BCH-19-001. The studies were also supported by the Rosamund Stone Zander Translational Neuroscience Center and the Intellectual and Developmental Disabilities Research Center (IDDRC) NIH/NICHD P50HD105351.

Author information

Author notes

  1. Kinga Gawlinska

    Present address: Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland

  2. These authors contributed equally: Angelica D’Amore, Maria Sundberg, Rui Lin.

Authors and Affiliations

  1. Department of Neurology, FM Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, USA

    Angelica D’Amore, Maria Sundberg, Rui Lin, Ella T. Lubbers, Kellen D. Winden, Lucy Yu, Kinga Gawlinska, Dawid Gawlinski, Sam G. Lopez, Yongho Choe, Emma V. Wightman, Yini Liang, Meera Modi, Christopher J. Yuskaitis, Henry Hing Cheong Lee, Alexander Rotenberg & Mustafa Sahin

  2. Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Boston, USA

    Christopher J. Yuskaitis & Alexander Rotenberg

  3. Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, USA

    Henry Hing Cheong Lee & Mustafa Sahin

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Contributions

AD, MS, HL, MM, AR, MS: design and concept of the study; AD, MS, RL, ETL, KDW, KG, DG, LY, SGL, YL, EVW, YL, HL, CJY: experimental data collection and analysis; AD, MS, RL, HL, MS: writing of the manuscript, editing, and revising the study.

Corresponding author

Correspondence to Mustafa Sahin.

Ethics declarations

Competing interests

HL and AR are co-founders of Galibra Neuroscience, Inc., and have equity in this company. Galibra Neuroscience, Inc. does not sponsor any part of this study. M. Sahin reports grant support from Biogen, Astellas, Bridgebio, and Aucta. He has served on Scientific Advisory Boards for Roche, SpringWorks Therapeutics, Jaguar Therapeutics and Alkermes.

Ethics approval and consent to participate

No human material or data were used in this study, therefore no consent forms were needed. Animal studies and all procedures here described involving animals were conducted in accordance with the Institutional Animal Care and Use Committee (IACUC) at Boston Children’s Hospital (#00002261). All experiments were conducted following approved laboratory SOPs and the approved Institutional Biosafety Committee (IBC) protocols at Boston Children’s Hospital (#07-164 & #P00001858).

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D’Amore, A., Sundberg, M., Lin, R. et al. Phenotypic rescue via mTOR inhibition in neuron-specific Pten knockout mice reveals AKT and mTORC1-site specific changes. Mol Psychiatry 30, 3077–3089 (2025). https://doi.org/10.1038/s41380-025-02916-2

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