TY - JOUR
T1 - Characterization of a commonly used mouse model of SMA reveals increased seizure susceptibility and heightened fear response in FVB/N mice
AU - Gogliotti, Rocky G.
AU - Lutz, Cathleen
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
Y1 - 2011/7
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.
KW - Metabotropic glutamate receptor 7
KW - Mouse
KW - Neurodegeneration
KW - SMA
KW - Seizure
KW - Spinal muscular atrophy
UR - http://www.scopus.com/inward/record.url?scp=79955951003&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955951003&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2011.03.002
DO - 10.1016/j.nbd.2011.03.002
M3 - Article
C2 - 21396450
AN - SCOPUS:79955951003
SN - 0969-9961
VL - 43
SP - 142
EP - 151
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1
ER -