A behavioral evaluation of sex differences in a mouse model of severe neuronal migration disorder

Abstract

Disruption of neuronal migration in humans is associated with a wide range of behavioral and cognitive outcomes including severe intellectual disability, language impairment, and social dysfunction. Furthermore, malformations of cortical development have been observed in a number of neurodevelopmental disorders (e.g. autism and dyslexia), where boys are much more commonly diagnosed than girls (estimates around 4 to 1). The use of rodent models provides an excellent means to examine how sex may modulate behavioral outcomes in the presence of comparable abnormal neuroanatomical presentations. Initially characterized by Rosen et al. 2012, the BXD29- Tlr4(lps-2J) /J mouse mutant exhibits a highly penetrant neuroanatomical phenotype that consists of bilateral midline subcortical nodular heterotopia with partial callosal agenesis. In the current study, we confirm our initial findings of a severe impairment in rapid auditory processing in affected male mice. We also report that BXD29- Tlr4(lps-2J) /J (mutant) female mice show no sparing of rapid auditory processing, and in fact show deficits similar to mutant males. Interestingly, female BXD29- Tlr4(lps-2J) /J mice do display superiority in Morris water maze performance as compared to wild type females, an affect not seen in mutant males. Finally, we report new evidence that BXD29- Tlr4(lps-2J) /J mice, in general, show evidence of hyper-social behaviors. In closing, the use of the BXD29- Tlr4(lps-2J) /J strain of mice - with its strong behavioral and neuroanatomical phenotype - may be highly useful in characterizing sex independent versus dependent mechanisms that interact with neural reorganization, as well as clinically relevant abnormal behavior resulting from aberrant neuronal migration.

Figure 1. Histological examination of Nissl stained coronal sections in BXD29-Tlr4^lps−2J/J mutant and BXD29/Ty wildtype mice.

A) Bilateral midline subcortical nodular heterotopia are present in all BXD29-Tlr4^lps−2J/J mutant mice. Black arrows indicate the boundaries of the abnormal clustering of cells within the coronal plane. B) Visualization of both male and female BXD29/Ty wildtype brains show no evidence of abnormal gross neuromorphology.

Figure 2. Auditory processing of BXD29-Tlr4^lps−2J/J mutant and BXD29/Ty wildtype mice.

A) Assessment of baseline auditory pre-pulse inhibition indicated comparable hearing and pre-pulse inhibition ability across Sex and Strain. Note, a lower attenuation score indicates better auditory pre-pulse inhibition ability. B) Silent Gap 0–300 ms and C) Silent Gap 0–100 ms gap detection tasks showed that BXD29-Tlr4^lps−2J/J mutant mice were specifically impaired in rapid auditory processing. The lack of Sex × Strain interaction signified no sex differences in RAP across both tasks, suggesting that female BXD29-Tlr4^lps−2J/J mutant mice did not exhibit a behavioral sparring of rapid auditory processing ability.

Figure 3. Rotarod performance of BXD29-Tlr4^lps−2J/J mutant and BXD29/Ty wildtype mice.

No main effect of Strain or Sex × Strain interaction was observed on the rotarod task, demonstrating the lack of sex differences in the BXD29-Tlr4^lps−2J/J strain of mice.

Figure 4. Morris water maze performance of BXD29-Tlr4^lps−2J/J mutant and BXD29/Ty wildtype mice.

A) Overall analysis of Morris water maze performance revealed a main effect of Sex and Sex × Strain interaction. B) Further post-hoc analysis indicated that the main effects of Sex and Sex × Strain interaction were pulled by the significantly better Morris water maze performance of female BXD29-Tlr4^lps−2J/J mutant mice in comparison to both male BXD29-Tlr4^lps−2J/J mutant mice and female BXD29/Ty wildtype mice. *P<0.05.

Figure 5. Examination of behavioral response to different social contexts in BXD29-Tlr4^lps−2J/J mutant and BXD29/Ty wildtype mice.

A) Analysis of male BXD29-Tlr4^lps−2J/J and BXD29/Ty ultrasonic vocalization emissions when exposed to seven-day-old dirty female bedding demonstrated that male BXD29-Tlr4^lps−2J/J mutant mice spent significantly more time vocalizing in response to dirty female bedding in comparison to male BXD29/Ty wildtype mice. B) Social preference data revealed a nearly significant trend that suggested BXD29-Tlr4^lps−2J/J mutant mice, in general, may prefer increased social interaction with a stranger mouse in comparison to a novel inanimate object. #P = 0.1; ***P<0.001.