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Published in final edited form as: Neurosci Lett. 2016 Dec 18;638:175–180. doi: 10.1016/j.neulet.2016.12.038

Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice

Alyssa R Toia 1, Joshua A Cuoco 1, Anthony W Esposito 1, Jawad Ahsan 1, Alok Joshi 1, Bruce J Herron 2,3, German Torres 1, Valerie J Bolivar 2,3, Raddy L Ramos 1
PMCID: PMC5239770  NIHMSID: NIHMS839139  PMID: 27993709

Abstract

Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1A/J/NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination.

Keywords: neocortex, malformation, heterotopia, C57BL/6

Introduction

The neocortex is highly vulnerable to neurodevelopmental malformations caused by a neuronal migration defect. Malformations characterized by incomplete migration, such as periventricular nodular heterotopia (PVH) [1–3] and subcortical band heterotopia (SBH) [4–7], have been extensively studied. In contrast, much less is known about neocortical molecular layer heterotopia (MLH), which are characterized by over-migration of neurons into the molecular layer (layer I) and present in disorders such as dyslexia [8–10] and epilepsy [11,12]. Greater understanding of MLH has implications for various disorders with diverse clinical presentations.

MLH are present in several knockout (KO) lines [13–22] and inbred mouse strains [23,24], including C57BL/6 and C57BL/10 mice [25–27]. The cytoarchitecture of MLH in mice is indistinguishable from human heterotopia, suggesting similar causal mechanisms. Moreover, mice with heterotopia exhibit impaired learning of spatial and non-spatial memory tasks [28–32] and deficits in sensory discrimination tasks [33–36], consistent with cognitive deficits associated with MLH. Furthermore, mice with MLH have lower seizure thresholds and shorter latency to seizures following chemi-convulsant treatment [37,38], which mimic brain excitability changes observed in epileptics with MLH. Thus, behavioral changes in mice with MLH closely resemble those observed in humans with MLH, demonstrating the utility of mice as a model of human MLH.

The prevalence of MLH and underlying mechanisms of heterotopia formation remain unclear. In this study, we performed a neuroanatomical survey for the presence of MLH using 6 widely-used inbred mouse strains, including strains commonly used to produce genetically-engineered (GE) mice. We investigated the basic inheritance patterns of MLH by examining 2 first filial generation (F1) hybrids, one consomic strain, and GE mice on a congenic C57BL/6 background. Our results indicate MLH formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant for understanding neocortical development and the mechanisms of cortical lamination. Since C57BL/6 is the most widely used inbred strain in neuroscience research, our results have broad implications for their use in diverse studies and the creation of GE mice.

Materials and methods

This study was carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All procedures were approved by the Institutional Animal Care and Use Committee of New York Institute of Technology and Wadsworth Center. Description of the housing and care of mice has been described previously [25,26,39,40]. Five week-old, A/J, DBA/2J, and B6D2F1/J male mice were obtained from The Jackson Laboratory (Bar Harbor, ME). Five week-old, 129S6/SvEvTac and B6129SF1/Tac male mice were obtained from Taconic Farms (Germantown, NY). Breeding pairs of 129S1/SvImJ, FVB/NJ, BALB/cJ inbred mice, and C57BL/6J-Chr 1A/J/NaJ (which carry chromosome 1 from strain A/J on a C57BL/6J background) were obtained from The Jackson Laboratory to generate mice used in this study. Brains from male and female retired breeders (≥ 6 months-old) or male and female offspring from these strains (≥ 3 weeks-old) were used. Since MLH are visible as early as P2 and the presence/absence of heterotopia does not change with age [25], we compared heterotopia prevalence between groups of mice because all mice were ≥ 3 weeks-old at time of sacrifice. Data from male and female mice were combined since MLH prevalence does not differ between sexes [25,26]. Finally, no differences in heterotopia prevalence were previously observed between mice obtained directly from commercial vendors and mice bred in an academic vivarium from commercially-obtained breeders [25,26].

Histological and analytical methods were previously described by our lab [25,26,39]. We also used digital histological data from the Allen Brain Atlas (ABA; www.brain-map.org) and Mouse Brain Architecture Project (MBAP; http://mouse.brainarchitecture.org) to document heterotopia as previously described [25,27,39,41,42]. Data from the ABA Mouse Strains dataset contains high-resolution sagittal and coronal sections from the following strains (The Jackson Laboratory): 129S1/SvlmJ, C57BL/6J, Cast/EiJ, DBA/2J, PWD/PhJ, SPRET/EiJ, WSB/EiJ. Methods used in the creation of the Mouse Strains dataset were previously reported [43]. Data from the ABA Transgenic Characterization dataset (http://connectivity.brain-map.org/transgenic) contains histology from 221 Cre-driver lines that have been crossed with one of 38 “reporter” mouse lines (loxP, etc.). Methods and mice used in the creation of the Transgenic Characterization dataset were previously described [44,45]. Data from the MBAP Transgenic Cell Counts dataset (http://mouse.brainarchitecture.org/cellcounts/) contains histology from 79 F1 hybrid mice generated by crosses between Cre-driver lines and reporter lines (loxP, etc.). Methods and mice used in the creation of the Transgenic Cell Counts dataset were found on the MBAP website.

Results

Prevalence of MLH in common inbred strains

The prevalence of MLH in C57BL/6J and C57BL/10J strains is well established [25–27], but only a small number of brains from a few other inbred mouse strains have been examined [25]. Consequently, we used well-established histological methods [25–27] to examine brains from numerous inbred mice including: 129S6/SvEvTac (n=20), 129S1/SvImJ (n=17), A/J (n=17), BALB/cJ (n=16), DBA/2J (n=20), FVB/NJ (n=18) strains. We used methods previously described [25,27,39,41,42] to examine high-resolution digital histological material from the Mouse Strains dataset from the ABA, including 129S1/SvImJ (n=117 cases), C57BL/6J (n=314), Cast/EiJ (n=117 cases), DBA/2J (n=117 cases), PWD/PhJ (n=93 cases), SPRET/EiJ (n=117 cases), WSB/EiJ (n=93 cases) strains. Remarkably, we did not observe MLH in any inbred strain except C57BL/6J brains in the ABA Mouse Strains dataset. Additionally, heterotopia were not observed in DBA/2J or 129S1/SvImJ mice in the ABA or in the cohort examined using primary histological data. This suggests that causal alleles for heterotopia formation are present in C57BL/6 linage.

Inheritance of MLH in the C57BL/6 linage

Since first filial generation (F1) hybrid mice are heterozygous at all loci where the parental strains differ in allelic composition, we examined F1 hybrid mice to determine if MLH formation is a recessive trait. After establishing that DBA/2J mice and 129S6/SvEvTac mice do not exhibit MLH, we tested whether F1 hybrid crosses of these inbred strains with C57BL/6 mice would exhibit heterotopia. We did not observe MLH in 20 male B6D2F1/J or 20 male B6129SF1/Tac mice, which were generated by crossing a female C57BL/6 mouse with a male DBA/2J mouse or male 129S6/SvEvTac mouse, respectively. This indicates that homozygosity, at one or more loci, is required for heterotopia formation.

Since consomic strains are characterized by the substitution of a homologous chromosome of a donor inbred strain backcrossed into a host inbred strain, they can be used to determine the chromosome associated with a given trait [46,47]. We examined brains from C57BL/6J-Chr 1A/J/NaJ mice, which have introgressed chromosome 1 from A/J on an inbred C57BL/6J background. We observed MLH in 6 out of 22 (27.27%) consomic mice. Fisher’s Exact Test of the prevalence of MLH in C57BL/6J-Chr 1A/J/NaJ mice compared to measures previously determined for C57BL/6J mice (35.71%) [26] revealed no significant difference. The absence of MLH in A/J mice indicates that the locus responsible for heterotopia formation is outside chromosome 1 of the C57BL/6 background.

Presence of MLH in genetically-engineered C57BL/6 congenic mice

These results suggest that GE mice produced from C57BL/6 ES cells and maintained on this background would exhibit MLH. Furthermore, GE mice produced from ES cells of another inbred strain but backcrossed to a C57BL/6 background would also exhibit MLH. We tested this prediction by examining over 1500 histological cases of F1 hybrid mice generated by crossing one of 221 Cre-driver lines with one of 38 reporter lines in the ABA Transgenic Characterization dataset. A total of 57 cases from this database exhibited MLH. Quantitative analyses of MLH prevalence were not performed because not every histological section is available for examination for each case. Thus, errors of omission (i.e. cases erroneously reporting absence of MLH) may explain the small number of cases of MLH in this dataset.

We identified 39 unique combinations of Cre-driver and reporter line hybrids with MLH as summarized in Figure 1 and Table 1. MLH were observed in F1 hybrids produced by crossing Pvalb-IRES-Cre mice with either Ai14 or Ai39 reporter mice and in F1 hybrids produced by crossing Emx1-IRES-Cre with either Ai27 or Ai32 reporter mice. All driver and reporter mice used to generate the F1 hybrids in Table 1 were identified as being on a congenic C57BL/6 background per the ABA, The Jackson Laboratory (jax.org), or the Mutant Mouse Resource and Research Center (mmrrc.org) websites. These data indicate a causal allele for heterotopia formation can be present in the background of diverse GE mice and inherited in F1 crosses of GE lines.

Figure 1.

Figure 1

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A–B, Representative photomicrographs of Nissl-stained sections with heterotopia (arrows) from C57BL/6J (from the ABA Mouse Strains dataset) and C57BL/6J-Chr 1A/J/NaJ mice (abbreviated B/6J-Chr11A/J/NaJ), respectively. C–F, Representative photomicrographs of adjacent sections of F1 hybrid lines taken from the Transgenic Characterization dataset of the ABA containing heterotopia (arrows). Nissl-stained and hybridized sections in left and right panels, respectively. Hybridized gene listed next to each photomicrograph taken from the ABA. Scalebars (in microns): A = 420, B = 320, C = 798, D = 960, E = 632, F = 444.

Table 1.

List of all unique driver-reporter F1 hybrid lines with MLH found in the ABA Transgenic Characterization dataset including experiment identification number of a representative example of each mouse line.

Experiment F1 Hybrid Line Name Driver line Reporter line
293795159 Avp-IRES2-Cre;Ai14 Avp-IRES2-Cre Ai14
175707182 Camk2a-tTA;Ai14 Camk2a-tTA Ai14
268328793 Chrnb4-Cre_OL57;Ai14 Chrnb4-Cre_OL57 Ai14
100132436 Crh-IRES-Cre (BL);Ai14 Crh-IRES-Cre (BL) Ai14
146455849 Crh-IRES-Cre (ZJH);Ai14 Crh-IRES-Cre (ZJH) Ai14
80203010 Cyp39a1-Tg1-Cre;R26-stop-EYFP Cyp39a1-Tg1-Cre R26-stop-EYFP
100141756 Dbh-Cre_KH212;Ai14 Dbh-Cre_KH212 Ai14
100141754 Drd1a-Cre;Ai14 Drd1a-Cre Ai14
175194677 EE313-lacZ-CreERT2-Tg2;Ai14 EE313-lacZ-CreERT2-Tg2 Ai14
167245573 EE342-lacZ-CreERT2-Tg3;Ai14 EE342-lacZ-CreERT2-Tg3 Ai14
167242744 EE609-lacZ-CreERT2-Tg2;Ai14 EE609-lacZ-CreERT2-Tg2 Ai14
167246779 EE921-lacZ-CreERT2-Tg2;Ai14 EE921-lacZ-CreERT2-Tg2 Ai14
100144601 Emx1-IRES-Cre;Ai32 Emx1-IRES-Cre Ai32
100095125 Emx1-IRES-Cre;Ai27 Emx1-IRES-Cre Ai27
100132637 Et(cre/ERT2)7089Rdav;Ai14 Et(cre/ERT2)7089Rdav Ai14
196126585 Et(EGFP/cre)16059Rdav;Ai14 Et(EGFP/cre)16059Rdav Ai14
100144041 Et(EGFP/cre)16102Rdav;Ai14 Et(EGFP/cre)16102Rdav Ai14
100141712 Et(EGFP/cre)16261Rdav;Ai14 Et(EGFP/cre)16261Rdav Ai14
156350546 Et(icre)21468Rdav;Ai14 Et(icre)21468Rdav Ai14
114374599 Et(icre/ERT2)14163Rdav;Ai14 Et(icre/ERT2)14163Rdav Ai14
100126208 Etv1-CreERT2;Ai14 Etv1-CreERT2 Ai14
157078989 Gabrr3-Cre_KC112;Ai14 Gabrr3-Cre_KC112 Ai14
100130925 Lepr-IRES-Cre;Ai14 Lepr-IRES-Cre Ai14
100132443 Ntsr1-Cre_GN220;Ai14 Ntsr1-Cre_GN220 Ai14
112608505 Otof-Cre;Ai14 Otof-Cre Ai14
159119080 Otof-CreERT2;Ai14 Otof-CreERT2 Ai14
100130512 Oxt-IRES-Cre;Ai14 Oxt-IRES-Cre Ai14
100144576 Pvalb-IRES-Cre;Ai39 Pvalb-IRES-Cre Ai39
100117968 Pvalb-IRES-Cre;Ai14 Pvalb-IRES-Cre Ai14
146454705 Rbp4-Cre_KL100;Ai14 Rbp4-Cre_KL100 Ai14
281575505 Slc17a7-IRES2-Cre;Ai14 Slc17a7-IRES2-Cre Ai14
100141516 Slc17a8-iCre;Ai14 Slc17a8-iCre Ai14
100104685 Slc6a3-Cre;Ai3 Slc6a3-Cre Ai3
112200098 Slc6a4-CreERT2_EZ13;Ai14 Slc6a4-CreERT2_EZ13 Ai14
181446571 Syt17-Cre_NO14;Ai14 Syt17-Cre_NO14 Ai14
146452634 Tac1-IRES2-Cre;Ai14 Tac1-IRES2-Cre Ai14
156348437 Trib2-2A-CreERT2;Ai14 Trib2-2A-CreERT2 Ai14
100141745 Ucn3-Cre_KF43;Ai14 Ucn3-Cre_KF43 Ai14
148054441 Vipr2-Cre_KE2;Ai14 Vipr2-Cre_KE2 Ai14
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MLH were also observed in the MBAP Transgenic Cell Counts database (Figure 2). Only 4 of 77 cases exhibited MLH which may be due to the mixed background in these congenic mice or fewer histological sections from which to evaluate. Nonetheless, heterotopia were identified in F1 hybrids crossed with the same Cre-driver mice shown to have MLH in the ABA database (e.g. Emx1-Cre and Pvalb-Cre mice). These data, from two different databases, indicate that driver-reporter F1 crosses can exhibit heterotopia.

Figure 2.

Figure 2

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A–D, Representative photomicrographs taken from F1 hybrid lines from the MBAP Transgenic Cell Counts database containing heterotopia (arrows). Nissl-stained and reporter protein expression shown in the left and right panels, respectively. Scalebar (in microns): A–B = 500; C–D = 600 microns.

Discussion

Heterotopia in the C57BL/6 linage require homozygosity at one or more alleles outside chromosome 1 and the sex chromosomes

We provide novel data on the prevalence and inheritance of spontaneous neurodevelopmental malformations of the neocortex using a combination of inbred and consomic strains as well as F1 hybrid GE mice. Our results indicate MLH may be unique to the C57BL linage as heterotopia were not observed in any other inbred strains examined. This suggests that other strains within the C57BL linage may also exhibit heterotopia, which is consistent with our previous observations of MLH in C57BL/10 mice. Since the natural history and genetic evolution/drift of this linage is well understood, documenting which C57BL stains exhibit MLH is instrumental toward a mechanistic understanding of heterotopia formation.

Using two different F1 hybrid mice produced from parental strains, including C57BL/6 and a strain with 0% prevalence for MLH (DBA/2J or 129S6/SvEvTac), our results indicate that homozygosity for one or more C57BL/6 alleles is required for heterotopia formation. This genetic model for heterotopia formation is consistent with observations of MLH in recombinant inbred mice, which by definition are homozygous at all alleles for some combination of each parental genotype [6,26,28–30,32]. Consequently, quantitative trait loci studies using a panel of recombinant inbred mice is a potential avenue to determine the genetic locus/loci responsible for MLH formation.

We used consomic mice to demonstrate that heterotopia formation requires one or more alleles outside of chromosome 1. Thus, future neuroanatomical analyses from an entire panel of consomic mice would reveal one or more strains that never exhibit heterotopia, thereby revealing the chromosome(s) where casual alleles are found. Since the prevalence of MLH in male and female C57BL/6 mice is the same [39] and F1 mice of both sexes do not display these malformations, these data argue that alleles on the sex chromosomes or chromosome 1 are not required for heterotopia formation.

Neocortical MLH in genetically-engineered mice

We document neocortical MLH in F1 hybrids of Cre-driver and reporter mouse lines even though most of these lines are on a mixed/congenic C57BL/6 background. The finding that MLH may be exclusive to the C57BL/6 linage suggests that heterotopia formation in these GE mice results from the inheritance of one or more causal C57BL/6 alleles during crossing. Consequently, GE mice created with C57BL/6 ES cells will exhibit some prevalence of heterotopia. Likewise, GE mice created with ES cells from another inbred strain but backcrossed to the C57BL/6 background will also exhibit heterotopia. Thus, results from studies using GE mice that exhibit heterotopia should be carefully evaluated so as not to attribute heterotopia formation to a genetic manipulation that was experimentally produced.

Implications of MLH on the use of C57BL/6J mice in neuroscience research

Our findings have broad implications on the use of C57BL/6 mice or GE mice on this background in neuroscience research. Firstly, results from neuroanatomical studies of neocortical development in C57BL/6 mice using experimental agents/perturbations to disrupt growth or neuronal migration should be carefully evaluated as some percentage of control and experimentally-treated mice are expected to exhibit heterotopia solely due to the genetic background. For example, in a study where C57BL/6 dams were treated with sodium acetazolamide, 34% of acetazolamide-exposed pups had heterotopia which was not significantly different than the 28% of water-treated control pups with heterotopia [48]. Secondly, results from behavioral studies using C57BL/6 mice or GE mice on this background should be carefully evaluated. Heterotopia in control and experimentally-treated mice may affect performance on the task(s) tested or interact with treatment regimes. This assertion is supported by previous findings that mice with MLH exhibit deficits in learning, memory [28–30,32], and sensory discrimination tasks [33,34,36] as well as neocortical hyperexcitability based on response to chemi-convulsant treatment [38,49]. Finally, the extent to which gene/protein expression changes are observed in neurons and glia in heterotopia remains unknown; these changes could affect neocortical expression studies, particularly when the presence/absence of heterotopia is not known prior to tissue harvesting. Thus, until the potential effects of neocortical MLH are elucidated, results from studies using C57BL/6 mice should be carefully evaluated. Histological confirmation of the presence/absence of heterotopia in mice used in a study would be critical to interpretation of experimental results.

Highlights.

  • Neocortical MLH is a weakly penetrant, divergent trait among inbred mice.

  • Homozygosity, at one or more loci, is required for the formation of heterotopia.

  • MLH formation requires one or more C57BL/6 alleles outside of chromosome 1.

  • MLH are present in diverse genetically-engineered lines on a C57BL/6 background.

Acknowledgments

This work was supported by NYIT departmental funds to R.L.R. and NIMH grant MH10368 to V.J.B. The authors thank the Veterinarian Sciences and Animal Care staff at NYIT and Wadsworth Center for the excellent care they provided for our mice.

Footnotes

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