Genetic dissection of susceptibility to audiogenic seizures in inbred mice.

Abstract

Mice of some inbred strains, such as 21-dayold DBA/2J mice, have generalized convulsions when exposed to intense auditory stimulation. Analysis of susceptibility to audiogenic seizures in BXD recombinant inbred strains has demonstrated the influence of at least three loci. One locus, Asp-], is located on chromosome 12 between Ah and D12Nyul; another locus, Asp-2, is on chromosome 4, tightly linked to b.Here we report evidence that Asp-2 is located within an 8-centimorgan segment distal to b and that Asp-3 is linked to Mtv-1 on chromosome 7. We also present evidence that these three loci account for most of the heritable variation in susceptibility to audiogenic seizures in crosses of DBA/2J and C57BL/6J mice and that susceptibility to audiogenic seizures is influenced by genomic imprinting. Thus, genomic imprinting may complicate linkage and mapping studies and should be considered in analyses of complex modes of inheritance.Convulsive seizures can be induced in experimental animals by intense auditory stimuli (1, 2). Susceptibility to audiogenic seizures (AS) varies widely between inbred strains of mice (2,3). The genetic basis for the difference in susceptibility to AS between DBA and C57BL mice has been studied several times since the strain difference was discovered by Hall (1). The typical AS consists of wild running followed by a clonic seizure and then a tonic seizure that is usually fatal, unless the mouse is resuscitated (1, 2, 4). DBA/2J (D2) mice are susceptible from 14 to 42 days of age with peak sensitivity at 21 days (5), whereas C57BL/6J (B6) mice are resistant to intense auditory stimuli. Variation in AS susceptibility has been attributed to a single locus (6-8), two loci (9, 10), and multifactorial (or polygenic) modes of inheritance (11)(12)(13)(14). The differing conclusions of these investigators can be attributed to many causes, including the use of different DBA and C57BL sublines, mice of different ages, and different experimental protocols (4, 15, 16).Testing of the BXD series of recombinant inbred (RI) strains and F1 hybrids from crosses between BXD RI strains and D2 revealed that at least three loci are involved in the genetic variation in AS susceptibility in crosses between D2 and B6 mice (14). Two of these loci have already been given chromosomal assignments. Asp-] (audiogenic seizure prone-1, formerly Ias) is tightly linked to the Ah locus on chromosome 12 (13,14,17), and Asp-2 (formerly asp) is located on chromosome 4 (7, 8), tightly linked to b (brown) (14).Here we report the mapping of Asp-3 by a reevaluation of published data (8,13,14,(17)(18)(19) in the light of advances in our understanding of the mode of inheritance of susceptibility to AS in crosses of D2 and B6 mice. We also report the results of reciprocal backcrosses that confirm the conclusions of the genetic dissection. MATERIALS AND METHODSThe data from two multipoint crosses reported by Collins (8) were recompiled and reexamined in an attempt to place Asp-2 on the linkage map (see Tables 1 and 2). In the firs...

5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice

“…Several analyses have detected seizure susceptibility QTLs on mid-chromosome 4 (Neumann and Collins, 1991;Martin et al, 1995;Ferraro et al, 1997) in mice, although most are still suggestive associations and mapped to relatively large regions. For convulsions associated with the alcohol and barbiturate withdrawal syndromes, positional cloning, sequence and expression analyses identify the multi-PDZ domain protein gene, Mpdz, as the most compelling gene within the critical 1.8 Mb chromosomal segment of chromosome 4 .…”

“…Animal models and QTL analyses provide powerful tools to dissect key sites of neuronal excitability and to identify the underlying genetic factors (Flint, 2003). QTL analyses in common inbred strains of mice have identified seizure susceptibility loci on mid-chromosome 4, including QTLs for convulsions elicited by chemical, electrical and audiogenic stimuli (Neumann and Collins, 1991;Martin et al, 1995;Ferraro et al, 1997) as well as alcohol and drug withdrawal convulsions elicited by handling (Buck et al, 1997(Buck et al, , 1999Fehr et al, 2002;Bergeson et al, 2003;Shirley et al, 2004). Thus, a gene or genes on mid-chromosome 4 may have pleiotropic effects on multiple seizure phenotypes.…”

Audiogenic Seizures - Biological Phenomenon and Experimental Model of Human Epilepsies

“…The identification of Asp loci in DBA/2J mouse strain had been possible on the basis of AE susceptibility scores in F2 hybrids of C57BL.6J (resistant) and DBA/2J susceptible strains (Neumann & Collins, 1991). The chromosomal location of three Asp (audiogenic seizure proneness) loci was determined by means of classical genetics approach (Fuller et al, 1950).…”

Genetic Networks Modulating Retinal Injury

“…PUM2 pull-down methods combined with RT-PCR confirmed that PUM2 does indeed bind P2P-R mRNA [Scott et al, 2005]. In regards to retinal healing, the GeneNework data are of interest because the BXD RI mouse strains segregate phenotypic differences in audiogenic seizures, hearing loss, and neurogenesis in the adult hippocampus [Willott and Erway, 1998;Kempermann and Gage, 2002;Neumann and Collins, 1991].…”

“…The C57BL/6 allele for the locus is one of the loci associated with resistance to noised-induced cell death of spiral ganglion cells, the cells innervating auditory receptors cells [GeneNetwork ID 10652 and 10655; Willott and Erway, 1998]. The DBA/2J allele of this locus also predisposes susceptibility to generalized convulsions when exposed to intense auditory stimulation [GeneNetwork ID 10434-5, 10437-8, and 10504;Neumann and Collins, 1991]. In contrast, the C57BL/6 allele is one of the loci that confers enhanced neurogenesis and survival of new neurons and astrocytes in adult hippocampus [GeneNetwork ID 10338, 10340-1, and 10378; Kempermann and Gage, 2002].…”