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

Document Type

Article

Publication Date

7-2011

Keywords

Animals, Disease Models, Animal, Epilepsy, Fear, Genetic Predisposition to Disease, Genome, Integration Host Factors, Introns, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscular Atrophy, Spinal, Receptors, Metabotropic Glutamate, Survival Analysis, Transgenes

JAX Source

Neurobiol Dis 2011; 43(1):142-51.

PMID

21396450

Volume

43

Issue

1

First Page

142

Last Page

151

ISSN

1095-953X

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 (+54s if Smn(+/+), +90s 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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