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

Ki Chan Kim, Jeehae Rhee, Jong Eun Park, Dong Keun Lee, Chang Soon Choi, Ji Woon Kim, Han Woong Lee, Mi Ryoung Song, Hee Jeong Yoo, Chi Hye Chung, Chan Young Shin

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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.

Original languageEnglish
Pages (from-to)7312-7328
Number of pages17
JournalMolecular Neurobiology
Volume53
Issue number10
DOIs
Publication statusPublished - 2016 Dec 1

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

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    Kim, K. C., Rhee, J., Park, J. E., Lee, D. K., Choi, C. S., Kim, J. W., Lee, H. W., Song, M. R., Yoo, H. J., Chung, C. H., & Shin, C. Y. (2016). Overexpression of Telomerase Reverse Transcriptase Induces Autism-like Excitatory Phenotypes in Mice. Molecular Neurobiology, 53(10), 7312-7328. https://doi.org/10.1007/s12035-015-9630-3