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.
Bibliographical noteFunding Information:
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).
All Science Journal Classification (ASJC) codes
- Cellular and Molecular Neuroscience