Differential regulation of the glutamate transporter variants GLT-1a and GLT-1b in the cortex and spinal cord of transgenic rats expressing hSOD1G93A

• GLT-1a and GLT-1b transcripts show different regulation profiles in ALS rats.
• In the cortex, GLT-1a mRNA is strongly decreased during the progression of ALS.
• In contrast, GLT-1b mRNA increases to reach a similar level as GLT-1a at end-stage.
• Both isoforms are strongly decreased in the ventral horns of transgenic rats.
• EAAC1 mRNA shows high expression at a pre-symptomatic stage in ALS animals.

Altered expression and activity of GLT-1 have been characterized in amyotrophic lateral sclerosis (ALS) patients and in animal models of the disease. Data suggest that the expression of two C-terminus splice variants of GLT-1 (namely GLT-1a and GLT-1b) can be differentially regulated in this pathological context. We herein characterized the expression of GLT-1a and GLT-1b mRNA and the glutamate uptake activity in the fronto-temporal cortex and the lumbar spinal cord of transgenic rats expressing hSOD1G93A at various stages of the disease. We also investigated the expression and activity of the other key glutamate transporters GLAST and EAAC1. While the progression of the disease was associated with a reduction of the overall GLT-1 activity in both cortex and spinal cord, the regulation of GLT-1a and GLT-1b transcripts showed different profiles. In the cortex, GLT-1a mRNA which appears as the most abundant isoform at a pre-symptomatic stage was strongly decreased during the progression of the disease while GLT-1b mRNA increased to reach a similar level as GLT-1a at end-stage. In the lumbar spinal cord of transgenic rats, both GLT-1a and GLT-1b mRNAs, expressed at the same levels before the symptom onset, were strongly decreased in the ventral horns. While no modification of GLAST was detected, EAAC1 mRNA was highly increased at a pre-symptomatic stage in transgenic animals, explaining a higher activity of glutamate transporters at this age. These results demonstrate that glutamate transporters are differentially expressed in nervous structures of wild-type and transgenic animals although the total GLT-1 activity was constantly decreased during the disease progression.