Selected Fast and Slow methionine sulfoximine-inbred mice: MSO-dependent seizures, behavior, brain glycoprofiles, neurotransmitters and glycogen

Methionine sulfoximine (MSO) was a side product of oxidation of methionine during bleaching of wheat for feeding animals. Such a compound was reported as altering animal behavior. Among these alterations, MSO was described as inducing epilepsy in variety of animals, and as glycogenic with a specific effect in brain. In order to study the putative relationships between these two effects, we 1) analyzed the concomitant effect of MSO in seizures and brain glycogen content in various strains of mice, and 2) developed mice strains based upon the latency to MSO-dependent generalized convulsions named MSO-Fast, for mice that displayed fast latency, and MSO-Slow, for mice that displayed very long latency. In mice we have selected, during various stages of selection processes, we studied the responses toward MSO in terms of seizures, brain neurotransmitter and glycogen contents, behavior, and glyco-profile of brain cortical astrocyte cell membrane proteins. In terms of MSO sensitivity, MSO-Fast mice have a very short latency toward MSO-dependent seizures as compared to MSO-Slow ones. In inbred mice, the latency of MSO-Fast is 277.6 ± 64.5 (n=20) minutes using 75mg/kg MSO, with this MSO dose no MSO-Slow mice convulsed during the first 10 hours. These data were confirmed by EEG. Kainic acid was the only other convulsant that demonstrated a significant difference between the two strains of mice, MSO-Fast being significantly more reactive than MSO-Slow ones (MSO-Fast: 42 ± 30 min; MSO-Slow: 75 ± 52 min, p<0.05, n=20). MSO-dependent seizures in MSO-Fast mice were significantly antagonized by MK-801. Therefore, we proposed that glutamatergic pathway is relevant in MSO-dependent seizures in our model of MSO-Fast and MSO-Slow mice. The behavior of MSO-Fast, observed by open field and learning capacity, demonstrated a more anxious behavior in MSO-Fast mice compared to MSO-Slow ones. The observed differences may find origin in alteration of 5-HT contents. This hypothesis was validated by quantization of 5-HT content in MSO-Fast mice (1.48 ± 0.65 pmole/mg prot) compared to MSO-Slow ones (0.59 ± 0.31 pmole/mg prot, p<0.01, n=8), using reversed-phase HPLC coupled to electro-chemical detection, The glycogen basal content is significantly higher in MSO-Fast mice (8.4 ± 1.5 nmole glucosyl/mg prot) compared to MSO-Slow ones (3.2 ± 1.0 nmole glucosyl/mg prot, p<0.001, n=10). Time course increase in glycogen content induced by MSO administration to mice is significantly higher in MSO-Fast mice than in MSO-Slow ones, while no significant variation was detected in both strain during control kinetics. These differences might explain what we observed in terms of glycosylation according to the lectins glycoprofiling results obtained in in vitro (cultured astrocytes). We concluded from the above experiments that the developed model of MSO-Fast and MSO-Slow inbred mice might be relevant to study the MSO-dependent seizures mechanism and the inter-relationships between seizure sensitivity and brain glycogen content. Our current hypothesis suggests that brain glycogen metabolism may constitute a defense against epileptic attack, as glycogen may be degraded down to glucose-6-phosphate that can be used to either postpone the epileptic seizures or to provide neurons with energy when they needed it. The ability of regulating this metabolism by variation of brain neurotransmitter contents, in particular the 5-HT neurotransmission, may constitute a defense against MSO-dependent epilepsy.