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Overexpression of Telomerase Reverse Transcriptase Induces Autism-like Excitatory Phenotypes in Mice

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Abstract

In addition to its classical role as a regulator of telomere length, recent reports suggest that telomerase reverse transcriptase (TERT) plays a role in the transcriptional regulation of gene expression such as β-catenin-responsive pathways. Silencing or over-expression of TERT in cultured NPCs demonstrated that TERT induced glutamatergic neuronal differentiation. During embryonic brain development, expression of transcription factors involved in glutamatergic neuronal differentiation was increased in mice over-expressing TERT (TERT-tg mice). We observed increased expression of NMDA receptor subunits and phosphorylation of α-CaMKII in TERT-tg mice. TERT-tg mice showed autism spectrum disorder (ASD)-like behavioral phenotypes as well as lowered threshold against electrically induced seizure. Interestingly, the NMDA receptor antagonist memantine restored behavioral abnormalities in TERT-tg mice. Consistent with the alteration in excitatory/inhibitory (E/I) ratio, TERT-tg mice showed autism-like behaviors, abnormal synaptic organization, and function in mPFC suggesting the role of altered TERT activity in the manifestation of ASD, which is further supported by the significant association of certain SNPs in Korean ASD patients.

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Acknowledgments

We would like to appreciate Dr. Daniel H. Geschwind for editing the manuscript and for the helpful discussion. This work was supported by the Korean Health Technology R&D project, Ministry of Health & Welfare, Republic of Korea (HI12C0021 0200), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (CY Shin, 2014R1A2A2A01003079).

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  1. Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea

    Ki Chan Kim, Chang Soon Choi, Ji-Woon Kim & Chan Young Shin

  2. Department of Biological Sciences, Konkuk University, Seoul, South Korea

    Jeehae Rhee & ChiHye Chung

  3. Department of Neuropsychiatry, Seoul National University Bungdang Hospital, Seongnam, South Korea

    Jong-Eun Park & Hee Jeong Yoo

  4. School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea

    Dong-Keun Lee & Mi-Ryoung Song

  5. School of Medicine, Konkuk University, Seoul, South Korea

    Chang Soon Choi, Ji-Woon Kim & Chan Young Shin

  6. KU Open Innovation Center, Konkuk University, Seoul, South Korea

    Chang Soon Choi, Ji-Woon Kim & Chan Young Shin

  7. Department of Biochemistry, College of Science, Yonsei University, Seoul, South Korea

    Han-Woong Lee

  8. Department of Pharmacology, School of Medicine and Center for Geriatric Neuroscience Research, IBST, Konkuk University, 1 Hwayang-Dong Kwang**-Gu, Seoul, 143-701, South Korea

    Chan Young Shin

Authors
  1. Ki Chan Kim
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  2. Jeehae Rhee
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  3. Jong-Eun Park
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  4. Dong-Keun Lee
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  5. Chang Soon Choi
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  6. Ji-Woon Kim
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  7. Han-Woong Lee
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  8. Mi-Ryoung Song
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  9. Hee Jeong Yoo
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  10. ChiHye Chung
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  11. Chan Young Shin
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Corresponding author

Correspondence to Chan Young Shin.

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Animal treatment and maintenance were carried out in accordance with the Principle of Laboratory Animal Care (NIH publication No. 85–23, revised 1985) and were approved by the Animal Care and Use Committee of the Konkuk University, Korea (KU12016 and KU12115).

Conflict of Interest

The authors declare that they have no competing interests.

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Kim, K.C., Rhee, J., Park, JE. et al. Overexpression of Telomerase Reverse Transcriptase Induces Autism-like Excitatory Phenotypes in Mice. Mol Neurobiol 53, 7312–7328 (2016). https://doi.org/10.1007/s12035-015-9630-3

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  • DOI: https://doi.org/10.1007/s12035-015-9630-3

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