i(3)so3-galactosylceramide and Seizures

Galactosylceramide (GalCer) and 3-O-sulfo-GalCer (sulfatide) are abundant sphingolipids in myelinating glial cells. However, low levels of GalCer and sulfatide have also been found in neurons, though their physiological role in these cells is unknown. Transgenic mice over-expressing UDP-galactose : ceramide galactosyltransferase (CGT) under control of the Thy1.2 promoter synthesize C18 : 0 fatty acid containing GalCer and sulfatide in neurons. Depending on the genetic background, these transgenic mice have a significantly reduced life span. Transgenic mice were extremely sensitive to sound stimuli and displayed lethal audiogenic seizures after relatively mild acoustic stimulation, i.e., key jangling. CGT-transgenic mice additionally over-expressing the adenosine 3'-phospho 5'-phosphosulfate : cerebroside sulfotransferase were more sensitive to audiogenic seizure induction than mice expressing only the CGT-transgene. This correlated with the higher sulfatide content in neuronal plasma membranes of the double-transgenic mice compared with CGT-transgenic mice, and strongly suggests that lethal audiogenic seizures are caused by elevated sulfatide levels in transgenic neurons. CGT-transgenic mice will be a useful model to further investigate how sulfatide affects functional properties of neurons.

Topics: Acoustic Stimulation; Animals; Brain; Epilepsy, Reflex; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurons; Seizures; Sulfoglycosphingolipids

Myelin was isolated from the brains of "quaking" and littermate control animals and its composition was determined. The brains of quaking animals contained approximately one-fourth as much myelin as the control animals. There were qualitative as well as quantitative differences between the myelin from the two groups. By continuous cesium chloride gradient flotation it was shown that the myelin from the quaking animals consisted solely of a band corresponding to the heavier and smaller of the two bands found in normal controls. Cholesterol and glycolipids were lower and phospholipids (mainly phosphatidylcholine) and protein were higher in quaking animals than in controls. Also, phosphatidal-ethanolamine was decreased, and several consistent differences in the fatty acids (both unsubstituted and hydroxy) and aldehydes of the component lipids were found. In general there were smaller amounts of monounsaturated fatty acids in quaking animals. We suggest from these findings that myelin in the quaking mouse has certain compositional similarities with juvenile myelin, but it may be an abnormal type of myelin.

Topics: Animals; Body Weight; Brain; Central Nervous System Diseases; Centrifugation, Density Gradient; Cerebrosides; Cholesterol; Chromatography, Gas; Chromatography, Thin Layer; Fatty Acids; Female; Mice; Mice, Inbred Strains; Mutation; Myelin Sheath; Organ Size; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids; Seizures; Sphingomyelins; Sulfoglycosphingolipids

Topics: Adolescent; Brain Diseases; Cerebrosides; Child; Chromatography; Humans; Infant; Infant, Newborn; Lipidoses; Mental Disorders; Seizures; Sulfates; Sulfoglycosphingolipids; Urine