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

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.

Sex Differences in Autism-Like Behavioral Phenotypes and Postsynaptic Receptors Expression in the Prefrontal Cortex of TERT Transgenic Mice

“…2A), as we also reported previously (Kim et al ., 2016b). The distance moved was not affected by genotype [F (1,60) =0.085, p= 0.772] nor according to sex [F (1,60) =0.4165, p= 0.521].…”

“…The autistic-like behavioral phenotypes found in the TERT-tg mice demonstrate a face validation of this model as what has been previously reported (Kim et al ., 2016b). More importantly, this study determined that only the male TERT-tg offspring but not their female littermates were affected.…”

“…We arranged the time of pregnancy during purchase so that FVB mice will give birth nearest to the time that the TERT-tg mice will give birth. The generation and identification of TERT-tg mice (FVB/N genetic background) along with their behavioral features was described previously (Kang et al ., 2004; Kim et al ., 2016b). Animals were kept in a room with automatic 12-h light cycle (lights on at 06:00), at a certain range of temperature (22 ± 2°C) and humidity (55 ± 5%).…”

“…In contrast, TERT knockout in mice resulted in a marked decline of neuronal stem cell proliferation along with specific impairments in neuronal differentiation and survival (Ferron et al ., 2009). Previously, we have reported that the TERT overexpressing transgenic mice (TERT-tg) have ASD-like behavioral phenotypes and have increased glutamatergic neuronal differentiation, increased postsynaptic protein expressions and increased excitability in the prefrontal cortex (Kim et al ., 2016b). All of these studies confirm the involvement of TERT in neuronal development and could be implicated in the excitatory/inhibitory imbalance theory of ASD (Rubenstein and Merzenich, 2003).…”

SRRintronic variation inhibits expression of its neighbouringSMG6 gene and protects against temporal lobe epilepsy

“…Significant telomerase activity was also observed in neuroprogenitor cells derived from the hippocampi of patients with TLE . More importantly, telomerase transgenic mice showed a lower threshold for electrically induced seizures, which could be reversed by the NMDA receptor antagonist memantine . These lines of evidence indicate a new role for telomerase in TLE that involves regulating NMDA receptor‐mediated excitatory disorders.…”