Abstracts

Rationale: Inbred strains of mice differ in their susceptibility to excitotoxin-induced cell death, but the genetic basis of individual variation is unknown. Previous studies using quantitative trait loci (QTL) mapping established that the distal region of mouse chromosome 18 [Sicd1] contains a gene(s) that is probably responsible for the difference in seizure-induced cell death susceptibility between two inbred strains, C57BL/6J and FVB/NJ. Previous studies have identified galanin receptor type 1 (GalR1) as a compelling candidate gene for this locus based on expression analysis (Kong et al., 2008) and its known role as a neuroprotective factor for the hippocampus. Thus, we wanted to examine the role of GalR1 in modulating seizure-induced excitotoxic cell death by utilizing GalR1 null mutant mice. Methods: GalR1^-/- mice were originally provided by Delta Lexicon and purchased from Jackson Laboratories. The mice were all first generation offspring resulting from the mating of C57BL/6JGalR1 ^/- females (N10-12) to C57BL/6JGalR1 ^/- males (N11-13). Young adult (GalR^{1 /} , GalR1^-/-, and C57BL/6J) mice received one subcutaneous injection of kainic acid (KA; Nanocs, NY). Following KA injections, mice were monitored continuously for 4 h for the onset of locomotor activity, behavioral manifestations of limbic seizure episodes, and scored for seizure activity as defined previously (Racine, 1972). Brains from animals in each age group were processed for light microscopic histopathologic evaluation seven days following kainate administration to evaluate the severity of seizure-induced brain damage. Results: Neither latency to onset of severe seizures nor duration of severe seizures was modulated by GalR1 genotype. However, GalR1^-/- mice showed increased susceptibility to seizure-induced cell death as compared to GalR1 wildtype mice. In particular, while KA administration into GalR1 ^/ mice generated no degeneration, KA administration into GalR1^-/- mice generated pronounced (2-fold) loss in areas CA3 and CA1 of the hippocampal formation. Similarly, we found a substantial increase in the extent of neuronal damage throughout the hippocampus of normally excitotoxin cell death-resistant mice (C57BL/6J) that received intra-hippocampal administration of the GalR1 antagonist, galantide, prior to kainate administration, as compared to those mice administered saline prior to kainate administration. Conclusions: Our results found that a reduction of GalR1 expression in the C57BL/6J mouse renders them susceptible to excitotoxic injury following systemic kainate administration. As well, we found a substantial increase in the extent of neuronal damage throughout the hippocampus of normally excitotoxic cell death-resistant mice (C57BL/6J) that received intra-hippocampal administration of the GalR1 antagonist prior to kainate administration. These results lend further support for the hypothesis that GalR1 can elicit a seizure-induced cell death susceptible phenotype.