An essential role for the H218/AGR16/Edg-5/LPB2 sphingosine 1-phosphate receptor in neuronal excitability

A wealth of indirect data suggest that the H218/AGR16/Edg-5/LPB2 sphingosin e 1-phosphate (S1P) receptor plays important roles in development. In vitro , it activates several forms of development-related signal transduction and regulates cellular proliferation, differentiation and survival. It is expr essed during embryogenesis, and mutation of an H218-like gene in zebrafish leads to profound defects in embryonic development. Nevertheless, the in vi vo functions served by H218 signalling have not been directly investigated. We report here that mice in which the H218 gene has been disrupted are une xpectedly born with no apparent anatomical or physiological defects. In add ition, no abnormalities were observed in general neurological development, peripheral axon growth or brain structure. However, between 3 and 7 weeks o f age, H218(-/-) mice have seizures which are spontaneous, sporadic and occ asionally lethal. Electroencephalographic abnormalities were identified bot h during and between the seizures. At a cellular level, whole-cell patch-cl amp recordings revealed that the loss of H218 leads to a large increase in the excitability of neocortical pyramidal neurons. Therefore, H218 plays an essential, unanticipated and functionally important role in the proper dev elopment and/or mediation of neuronal excitability.