Abstracts

RATIONALE: Patients and experimental models of temporal lobe epilepsy display loss of somatostatinergic neurons in the dentate gyrus. To determine if loss of the peptide somatostatin contributes to epileptic seizures we examined kainate-evoked seizures and kindling in somatostatin knockout (SSKO) mice. METHODS: A mutated Smst gene allele with deletion of promoter sequences and the first coding exon was generated by homologous recombination in embryonic stem cells. Germline penetrant chimeras (129P2/OlaHsd, C57BL/6J) were derived from these ES cells and subsequently the null allele was backcrossed for 5 generations onto the C57BL/6J genetic background. N5 congenic heterozygote mating pairs produced the mice used for this study. No somatostatin peptides could be measured by radioimmunoassay or immunohistochemistry in the brain or GI tract of SSKO mice. Control and SSKO mice were treated with kainate (25 mg/kg ip, n=25) which evokes limbic seizures, or kindled by daily electrical stimulation of the perforant path (n=24) to more specifically challenge the dentate gyrus. RESULTS: Timm staining, acetylcholinesterase histochemistry, immunocytochemistry for NPY, calbindin, calretinin, and parvalbumin, and optical fractionator counting of Nissl-stained hilar neurons (14,363 vs 14,093 per dentate gyrus, P>0.7) reveals no obvious compensatory changes or developmental abnormalities in the dentate gyrus of SSKO mice. In response to kainate, SSKO mice have slightly more severe seizures than controls. Their average latency to stage 5 seizures is shorter than controls (12.4 vs 22.8 min, P<0.07), their average maximal behavioral seizure score is higher (5.8 vs 4.7, P<0.05), and they are more likely to die (88 vs 56%, P<0.08). In response to kindling, mean afterdischarge duration in SSKO mice is slightly longer (19.7 vs 18.2 sec, P<0.07), but the number of treatments to 5 stage 4-5 seizures is similar to controls (17.9 vs 16.6, P>0.6). CONCLUSIONS: These findings suggest that somatostatin may be mildly anticonvulsant, but its loss alone is unlikely to account for seizures in temporal lobe epilepsy. Supported by Medical Research Foundation of Oregon, NIH (NS01778), and Burroughs Wellcome Fund.