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. 2000 Feb 29;97(5):2286-90.
doi: 10.1073/pnas.040469797.

The hippocampal neurons of neuronal apoptosis inhibitory protein 1 (NAIP1)-deleted mice display increased vulnerability to kainic acid-induced injury

M Holcik  1 , C S Thompson, Z Yaraghi, C A Lefebvre, A E MacKenzie, R G Korneluk
Affiliations

The hippocampal neurons of neuronal apoptosis inhibitory protein 1 (NAIP1)-deleted mice display increased vulnerability to kainic acid-induced injury

M Holcik et al. Proc Natl Acad Sci U S A. .

Abstract

The neuronal apoptosis inhibitory protein (NAIP) is a member of a novel family of inhibitor of apoptosis (IAP) proteins. The IAP genes are highly conserved from baculovirus to metazoans and suppress apoptosis induced by a variety of triggers both in vitro and in vivo. Here we describe the generation and characterization of mice with the targeted deletion of NAIP1. We demonstrate that the NAIP1-deleted mice develop normally. However, the survival of pyramidal neurons in the hippocampus after kainic acid-induced limbic seizures is greatly reduced in the NAIP1 knock-out animals. Thus, although NAIP1 is not necessary for normal development of murine central nervous system, the endogenous NAIP1 is required for neuronal survival in pathological conditions.

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Figures

Figure 1
Figure 1
Schematic diagram of the targeted disruption of the Naip1 gene in mice. (A) The structure of the 5′ end of the mouse Naip1 locus, targeting vector pKO.naip1, and the targeted Naip1 allele are shown. Solid boxes indicate exons; restriction sites are indicated by vertical black lines (E, EcoRI; RV, EcoRV; S, SstI). The position of the probe used for the genomic Southern blot analysis is indicated by the black box, and the positions of reverse transcription-PCR primers are indicated by arrowheads. (B) Southern blot analysis of EcoRI-digested genomic DNA from embryonic stem cells indicates the presence of the targeted (4.8 kb) and the wild-type (7.5 kb) alleles. (C) Southern blot analysis of EcoRI-digested genomic DNA from homozygous mutant (−/−), hetorozygous (+/−), and wild-type (+/+) Naip1 mice (line 249). (D) Reverse transcription-PCR analysis of brain mRNA for Naip1-null and wild-type mice. Naip1-specific PCR primers (21) were used to amplify Naip1 cDNA between exons 1 and 4. The 200-nt fragment of actin was amplified as a positive control.
Figure 2
Figure 2
Targeted disruption of Naip1 gene sensitizes CA3 neurons to KA-induced cell death. (A) Histopathologic changes in the CA3 region of dorsal hippocampus 72 hr after KA treatment (45 mg/kg; i.p.) of Naip1-deleted and wild-type mice. ISEL-positive CA3 neurons were detected as described in Material and Methods. Typical sections are shown. (B) Number of ISEL-positive CA3 neurons in the dorsal hippocampus differs between Naip1-deleted (n = 11) and wild-type (n = 14) mice. Cryostat sections from four different levels of the hippocampus in both hemispheres were ISEL-stained and the number of ISEL-positive CA3 pyramidal neurons nuclei was summed for each mouse [mean ± SD; *, P < 0.005 (one-way ANOVA)].
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