Frequent spontaneous seizures followed by spatial working memory/anxiety deficits in mice lacking sphingosine 1-phosphate receptor 2.
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.
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan.
Noriyuki
N
Akahoshi
Yasuki
Y
Ishizaki
Hiroki
H
Yasuda
Yoshiya L
YL
Murashima
Toshikazu
T
Shinba
Kaoru
K
Goto
Toshiyuki
T
Himi
Jerold
J
Chun
Isao
I
Ishii
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000502:physiology; D001921:Brain / Q000473:pathology; D001931:Brain Mapping; D004569:Electroencephalography; D020869:Gene Expression Profiling; D005911:Gliosis / Q000209:etiology / Q000235:genetics; D066298:In Vitro Techniques; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology*; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D049349:Receptors, Lysosphingolipid / Q000172:deficiency*; D012640:Seizures / Q000150:complications* / Q000235:genetics*; D013028:Space Perception / Q000502:physiology*; D000081025:Sphingosine-1-Phosphate Receptors; D014741:Video Recording
D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse