Characterization of a commonly used mouse model of SMA reveals increased seizure susceptibility and heightened fear response in FVB/N mice

Rocky G. Gogliotti; Cathleen Lutz; Michael Jorgensen; Kimberly Huebsch; Sookyong Koh; Christine J. DiDonato

doi:10.1016/j.nbd.2011.03.002

Characterization of a commonly used mouse model of SMA reveals increased seizure susceptibility and heightened fear response in FVB/N mice

Rocky G. Gogliotti, Cathleen Lutz, Michael Jorgensen, Kimberly Huebsch, Sookyong Koh, Christine J. DiDonato^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

The SMN2 transgenic mouse, Tg(SMN2)89Ahmb, has emerged as the most widely used in spinal muscular atrophy (SMA) research. Here we clone the genomic integration site of the transgene and demonstrate it to be in intron 4 of the metabotropic glutamate receptor 7 (mGluR7) gene. We found that the integration of this transgene significantly reduced both mGluR7 mRNA and protein levels (24% and 9%, respectively). To determine if phenotypes associated with mGluR7 knockout mice were present in Tg(SMN2)89Ahmb containing mice, we subjected mice homozygous for the transgene to open field and seizure susceptibility tests. When compared to wild type FVB/N mice, Tg(SMN2)89Ahmb ^tg/tg mice exhibited significantly longer times in finding a safe wall-adjacent square (+. 54. s if Smn ^+/+, +. 90. s if Smn ^+/-), as well as a significantly higher frequency of generalized seizure in response to a subthreshold dose of pentylenetrazol (0.11 vs 0.45). These findings aid in explaining the sudden unexpected death that occurs within SMA mouse colonies that contain a homozygous Tg(SMN2)89Ahmb transgene. This should be taken into account in pre-clinical studies that utilize this transgene, especially in therapy-treated SMA mice that have extended survival.

Original language	English (US)
Pages (from-to)	142-151
Number of pages	10
Journal	Neurobiology of Disease
Volume	43
Issue number	1
DOIs	https://doi.org/10.1016/j.nbd.2011.03.002
State	Published - Jul 2011

Funding

Funding : R.G. is supported by an NIH training grant [ T32 AG000260 ] “ Drug Discovery Training in Age-related Disorders .” Research support for these studies was provided by the Families of Spinal Muscular Atrophy DiD0809 , the NIH grants # 1ROIN5060926, 3RO1NS060926-02S3 ( NINDS ), and 1R21HD058311-01A1 ( NICHD ) to CJD and the SMA Foundation to C.L.

Keywords

Metabotropic glutamate receptor 7
Mouse
Neurodegeneration
SMA
Seizure
Spinal muscular atrophy

ASJC Scopus subject areas

Neurology

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10.1016/j.nbd.2011.03.002

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@article{3a4880d7f7d34062b349a6b9525eafab,

title = "Characterization of a commonly used mouse model of SMA reveals increased seizure susceptibility and heightened fear response in FVB/N mice",

abstract = "The SMN2 transgenic mouse, Tg(SMN2)89Ahmb, has emerged as the most widely used in spinal muscular atrophy (SMA) research. Here we clone the genomic integration site of the transgene and demonstrate it to be in intron 4 of the metabotropic glutamate receptor 7 (mGluR7) gene. We found that the integration of this transgene significantly reduced both mGluR7 mRNA and protein levels (24% and 9%, respectively). To determine if phenotypes associated with mGluR7 knockout mice were present in Tg(SMN2)89Ahmb containing mice, we subjected mice homozygous for the transgene to open field and seizure susceptibility tests. When compared to wild type FVB/N mice, Tg(SMN2)89Ahmb tg/tg mice exhibited significantly longer times in finding a safe wall-adjacent square (+. 54. s if Smn +/+, +. 90. s if Smn +/-), as well as a significantly higher frequency of generalized seizure in response to a subthreshold dose of pentylenetrazol (0.11 vs 0.45). These findings aid in explaining the sudden unexpected death that occurs within SMA mouse colonies that contain a homozygous Tg(SMN2)89Ahmb transgene. This should be taken into account in pre-clinical studies that utilize this transgene, especially in therapy-treated SMA mice that have extended survival.",

keywords = "Metabotropic glutamate receptor 7, Mouse, Neurodegeneration, SMA, Seizure, Spinal muscular atrophy",

author = "Gogliotti, {Rocky G.} and Cathleen Lutz and Michael Jorgensen and Kimberly Huebsch and Sookyong Koh and DiDonato, {Christine J.}",

note = "Funding Information: Funding : R.G. is supported by an NIH training grant [ T32 AG000260 ] “ Drug Discovery Training in Age-related Disorders .” Research support for these studies was provided by the Families of Spinal Muscular Atrophy DiD0809 , the NIH grants # 1ROIN5060926, 3RO1NS060926-02S3 ( NINDS ), and 1R21HD058311-01A1 ( NICHD ) to CJD and the SMA Foundation to C.L.",

year = "2011",

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AU - Jorgensen, Michael

AU - Huebsch, Kimberly

AU - Koh, Sookyong

AU - DiDonato, Christine J.

N1 - Funding Information: Funding : R.G. is supported by an NIH training grant [ T32 AG000260 ] “ Drug Discovery Training in Age-related Disorders .” Research support for these studies was provided by the Families of Spinal Muscular Atrophy DiD0809 , the NIH grants # 1ROIN5060926, 3RO1NS060926-02S3 ( NINDS ), and 1R21HD058311-01A1 ( NICHD ) to CJD and the SMA Foundation to C.L.

PY - 2011/7

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N2 - The SMN2 transgenic mouse, Tg(SMN2)89Ahmb, has emerged as the most widely used in spinal muscular atrophy (SMA) research. Here we clone the genomic integration site of the transgene and demonstrate it to be in intron 4 of the metabotropic glutamate receptor 7 (mGluR7) gene. We found that the integration of this transgene significantly reduced both mGluR7 mRNA and protein levels (24% and 9%, respectively). To determine if phenotypes associated with mGluR7 knockout mice were present in Tg(SMN2)89Ahmb containing mice, we subjected mice homozygous for the transgene to open field and seizure susceptibility tests. When compared to wild type FVB/N mice, Tg(SMN2)89Ahmb tg/tg mice exhibited significantly longer times in finding a safe wall-adjacent square (+. 54. s if Smn +/+, +. 90. s if Smn +/-), as well as a significantly higher frequency of generalized seizure in response to a subthreshold dose of pentylenetrazol (0.11 vs 0.45). These findings aid in explaining the sudden unexpected death that occurs within SMA mouse colonies that contain a homozygous Tg(SMN2)89Ahmb transgene. This should be taken into account in pre-clinical studies that utilize this transgene, especially in therapy-treated SMA mice that have extended survival.

AB - The SMN2 transgenic mouse, Tg(SMN2)89Ahmb, has emerged as the most widely used in spinal muscular atrophy (SMA) research. Here we clone the genomic integration site of the transgene and demonstrate it to be in intron 4 of the metabotropic glutamate receptor 7 (mGluR7) gene. We found that the integration of this transgene significantly reduced both mGluR7 mRNA and protein levels (24% and 9%, respectively). To determine if phenotypes associated with mGluR7 knockout mice were present in Tg(SMN2)89Ahmb containing mice, we subjected mice homozygous for the transgene to open field and seizure susceptibility tests. When compared to wild type FVB/N mice, Tg(SMN2)89Ahmb tg/tg mice exhibited significantly longer times in finding a safe wall-adjacent square (+. 54. s if Smn +/+, +. 90. s if Smn +/-), as well as a significantly higher frequency of generalized seizure in response to a subthreshold dose of pentylenetrazol (0.11 vs 0.45). These findings aid in explaining the sudden unexpected death that occurs within SMA mouse colonies that contain a homozygous Tg(SMN2)89Ahmb transgene. This should be taken into account in pre-clinical studies that utilize this transgene, especially in therapy-treated SMA mice that have extended survival.

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KW - Seizure

KW - Spinal muscular atrophy

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Characterization of a commonly used mouse model of SMA reveals increased seizure susceptibility and heightened fear response in FVB/N mice

Abstract

Funding

Keywords

ASJC Scopus subject areas

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