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

Abstract

Autism spectrum disorder (ASD) remains unexplained and untreated despite the high attention of research in recent years. Aside from its various characteristics is the baffling male preponderance over the female population. Using a validated animal model of ASD which is the telomerase reverse transcriptase overexpressing mice (TERT-tg), we conducted ASD-related behavioral assessments and protein expression experiments to mark the difference between male and females of this animal model. After statistically analyzing the results, we found significant effects of TERT overexpression in sociability, social novelty preference, anxiety, nest building, and electroseizure threshold in the males but not their female littermates. Along these differences are the male-specific increased expressions of postsynaptic proteins which are the NMDA and AMPA receptors in the prefrontal cortex. The vGluT1 presynaptic proteins, but not GAD, were upregulated in both sexes of TERT-tg mice, although it is more significantly pronounced in the male group. Here, we confirmed that the behavioral effect of TERT overexpression in mice was male-specific, suggesting that the aberration of this gene and its downstream pathways preferentially affect the functional development of the male brain, consistent with the male preponderance in ASD.

Sex-specific Behavioral Features of Rodent Models of Autism Spectrum Disorder

“…These observations were coupled with a reduction of MeCP2 expressions in both the prefrontal cortex of the male offspring and neuronal progenitor cells isolated by sex. We observed the same male bias in the TERT-tg mice, which shows autistic-like phenotypes, more pronounced increase in the expression of VGluT1, a presynaptic marker, and increases in postsynaptic markers of the NMDA and AMPA receptor subtypes [ 209 ].…”

Sex Differences in Psychiatric Disease: A Focus on the Glutamate System

“…Similar male-specific effects are seen in the telomerase reverse transcriptase overexpressing mice (TERT-tg). Male TERT-tg mice exhibit impaired social behavior, increased anxiety-like behavior, and lowered seizure threshold, while female TERT-tg mice do not (Kim et al, 2017 ). Maternal immune challenge also leads to male-specific deficits in social behavior in the contactin-associated protein-like 2 (Cntnap2) mouse model of ASD (Schaafsma et al, 2017 ).…”

Crmp4-KO Mice as an Animal Model for Investigating Certain Phenotypes of Autism Spectrum Disorders

“…In addition, telomerase reverse transcriptase-overexpressing (TERT transgenic, TERT-tg) mice exhibit male-specific autism-like behaviors, as well as increases in the expression of the NMDA receptor NR2A and NR2B subunits and AMPA receptor GluR1 and GluR2 subunits. TERT-tg mice also exhibit increases in vesicular glutamate transporter (vGluT) 1 levels in the prefrontal cortex [86]. Furthermore, research has indicated that glutamatergic modulators may aid in the treatment of ASD in humans [83,87] and animal models [85,88,89], supporting the notion that the glutamatergic system plays a role in ASD and ASD-like phenotypes.…”

“…For example, male-biased differences have been observed in patients with ASD exhibiting mutations in genes that encode the synaptic cell adhesion protein neuroligin ( NLGN), including NLGN 3, and NLGN4X [98,99]. Sex-based differences in autistic-like phenotypes have also been reported in animal models of ASD generated by exposure to chemicals or genetic manipulation [8,67,86,100,101,102,103]. For example, Schneider et al [102] demonstrated that prenatal exposure to valproic acid (VPA), which is well known to induce autism-like phenotypes in rats or mice [104], induces some male-specific alterations in behavior and immunological function.…”

“…For example, Schneider et al [102] demonstrated that prenatal exposure to valproic acid (VPA), which is well known to induce autism-like phenotypes in rats or mice [104], induces some male-specific alterations in behavior and immunological function. Kim et al [86,101] further revealed that rats exposed to VPA in utero exhibit male-specific alterations in social interactions, hyperactive behavior, and impaired postsynaptic development. Konopko et al [103] reported sex-based differences in the induction of some exons of the brain-derived neurotrophic factor (Bdnf) gene in the brains of fetal mice exposed to VPA during the prenatal period, indicating that female sex may confer neuroprotection against ASD-like phenotypes.…”