Elsevier

Brain Research

Volume 971, Issue 1, 2 May 2003, Pages 47-54
Brain Research

Research report
Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+ tf/tf has severely reduced hippocampal commissure and absent corpus callosum

https://doi.org/10.1016/S0006-8993(03)02354-0Get rights and content

Abstract

A morphometric survey of brain size and forebrain commissures of 21 inbred mouse strains from the Jackson Laboratory was done with animals tested in two laboratories as part of the Mouse Phenome Project. Strain BTBR T/+ tf/tf was found to have 100% total absence of the corpus callosum as well as severe reduction of the hippocampal commissure in almost every animal, the most severe commissure defect observed to date in any commercially available mouse strain. The strain 129S1/SvImJ had a milder defect with incomplete penetrance. Crosses of BTBR mice with inbred strains BALB/cWah1, 129P1/ReJ, and the recombinant strain 9XCA/Wah having a severe commissure defect supported a two-locus model of the genetic defect in these strains. Brain size varied greatly among strains but for any one strain was almost identical in mice housed for 5 weeks in the two laboratories. Sex differences in brain weight and forebrain commissure sizes were not statistically significant.

Introduction

Hereditary absence of the corpus callosum (CC) was first documented in laboratory mice by King and Keeler [6] in a stock that later became extinct, and it was rediscovered by Wimer [27] in the inbred strains BALB/cJ, 129P3/J, and I/LnJ [5]. Every BALB/c and 129-derived strain examined to date shows incomplete penetrance for the CC defect, whereas all I/LnJ mice suffer absent CC. About half of I/LnJ mice also exhibit severe reduction of the size of the hippocampal commissure (HC), a defect that is only seen in individuals lacking the CC [8]. The recombinant inbred strain 9XCA/Wah derived from the progenitors 129P1/ReJ and BALB/cWah1 has 100% total absence of the CC and severe reduction of the HC [23]. We now report that the inbred strain BTBR T/+ tf/tf has a phenotype more severe than I/LnJ and similar to 9XCA/Wah, which amounts to the most severe and consistent forebrain commissure defect known in commercially available strains. This discovery should facilitate the study of the genetics, developmental origins, and behavioral consequences of commissure defects.

The present study was done as part of the Mouse Phenome Project (MPP; http://www.jax.org/phenome), an extensive and intensive effort by more than a dozen laboratories to phenotype 40 inbred strains maintained at the Jackson Laboratory [12]. The 40 strains are divided into priority groups A, B, C, and D with ten strains each [20], chosen to represent a wide diversity of mouse genotypes. At the outset of the MPP in 1999, the highest priority group A included the little known strain BTBR T/+ tf/tf, but that strain was later moved by MPP staff to the lowest priority group D. Our work with behavioral tests in two laboratories began in 2000 with the original group A, and we found some interesting behavioral differences in the BTBR mice, especially their superior performance on the accelerating rotarod [14], [15]. Consequently, when we expanded our study in 2002 to include the 20 strains in priority groups A and B, we included BTBR from group D and assessed brain size and commissure anatomy of 21 inbred strains.

Section snippets

Mice

The inbred strains listed in Table 1 were obtained from the Jackson Laboratory, Bar Harbor, ME, at 7 weeks of age, tested for several behaviors at 10–12 weeks of age, and then examined for brain defects at ∼12.5 weeks. The mice were sent in five simultaneous shipments to the laboratories in Edmonton and Portland, with each shipment usually providing two or three mice per strain per laboratory. For any one shipment to a laboratory, all mice of a given strain were the same sex and could have been

Results

The Portland laboratory was able to test only females of the wild-derived strain SPRET/Ei, and a full three-way analysis of variance (ANOVA) involving strain, sex, and site was possible only for 20 of the 21 strains (Table 2). The analyses revealed a significant sex main effect only for body weight (males 4.3 g heavier). The site main effect for body weight (mean body weight 0.1 g heavier in Portland than Edmonton) was not significant (P=0.43). Although there was a significant strain×site

Discussion

Strain BTBR T/+ tf/tf has the most severe forebrain commissure defects of any strain from the Jackson Laboratory that has been examined in detail. Nevertheless, the strain breeds reasonably well [1], unlike the very difficult I/LnJ strain. It will therefore be useful for genetic, anatomical and behavioral research on the origin and role of the corpus callosum and hippocampal commissure. BTBR mice may prove especially valuable for investigating the role of the hippocampal commissure. The

Acknowledgements

This work was supported by the Mouse Phenome Project, NIH grants R01 AA12714 and AA10760, NSERC grant 45825, and a grant from the Department of Veterans Affairs. The authors are grateful to Brandie Moisan, Sean F. Cooper, Kim Seward, Simmone Kerswell, Jason Schlumbohm, Chia-Hua Yu, Andrew Forster, and Nathan Rustay for technical assistance.

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