Frequent spontaneous seizures followed by spatial working memory/anxiety deficits in mice lacking sphingosine 1-phosphate receptor 2

Abstract

The diverse physiological effects of sphingosine 1-phosphate (S1P) are mostly mediated by its five cognate G protein-coupled receptors, S1P(1)-S1P(5), which have attracted much attention as future drug targets. To gain insight into S1P(2)-mediated signaling, we analyzed frequent spontaneous seizures in S1P(2)-deficient (S1P(2)(-/-)) mice obtained after several backcrosses onto a C57BL/6N background. Full-time video recording of 120 S1P(2)(-/-) mice identified 420 seizures both day and night between postnatal days 25 and 45, which were accompanied by high-voltage synchronized cortical discharges and a series of typical episodes: wild run, tonic-clonic convulsion, freezing, and, occasionally, death. Nearly 40% of 224 S1P(2)(-/-) mice died after such seizures, while the remaining 60% of the mice survived to adulthood; however, approximately half of the deliveries from S1P(2)(-/-) pregnant mice resulted in neonatal death. In situ hybridization revealed exclusive s1p(2) expression in the hippocampal pyramidal/granular neurons of wild-type mice, and immunohistochemistry/microarray analyses identified enhanced gliosis in the whole hippocampus and its neighboring neocortex in seizure-prone adult S1P(2)(-/-) mice. Seizure-prone adult S1P(2)(-/-) mice displayed impaired spatial working memory in the eight-arm radial maze test and increased anxiety in the elevated plus maze test, whereas their passive avoidance learning memory performance in the step-through test and hippocampal long-term potentiation was indistinguishable from that of wild-type mice. Our findings suggest that blockade of S1P(2) signaling may cause seizures/hippocampal insults and impair some specific central nervous system functions.