Anti-SLC1A2 (aa 160-239) polyclonal antibody

Genetic polymorphisms in Solute carrier family 1 (glial high affinity glutamate transporter), member 2 (SLC1A2) have been linked with essential tremor. SLC1A2 encodes excitatory amino acid transporter type 2 (EAAT2), which clears glutamate from the synaptic cleft. One postulated mechanism for essential tremor is the over-excitation of glutamatergic olivo-cerebellar climbing fibers, leading to excitotoxic death of Purkinje cells. Other glutamatergic excitatory signals are transmitted to Purkinje cells via parallel fibers of cerebellar granule neurons. Therefore, the expression level of glutamate transporters could be important in essential tremor pathogenesis. Using Western blotting, we compared the expression levels of the two main glutamate transporters in the cerebellar cortex, EAAT1 and EAAT2, in postmortem tissue from 16 essential tremor cases and 13 age-matched controls. We also studied the localization of EAAT1 and EAAT2 using immunohistochemistry in 10 essential tremor cases and 12 controls. EAAT1 protein levels were similar in cases and controls (1.12 +/- 0.83 vs. 1.01 +/- 0.69, p = 0.71) whereas EAAT2 protein levels in essential tremor cases were only 1/3 of that in controls (0.35 +/- 0.23 vs. 1.00 +/- 0.62, p < 0.01). Interestingly, EAAT2, but not EAAT1, was expressed in astrocytic processes surrounding the Purkinje cell axon initial segment, a region of previously observed pathological changes in essential tremor. Our main finding, a significant reduction in cerebellar cortical EAAT2 protein levels in essential tremor, suggests that Purkinje cells in essential tremor might be more vulnerable to excitotoxic damage than those of controls.

Excitotoxicity contributes to epileptogenesis after severe traumatic brain injury (sTBI). Demographic and clinical risk factors for post-traumatic seizures (PTS) have been identified, but genetic risk remains largely unknown. Thus, we investigated whether genetic variation in astroglial glutamate transporter genes is associated with accelerated epileptogenesis and PTS risk after sTBI. Adults (n=267) 18-75 years old were assessed over a three-year period post-TBI. Single nucleotide polymorphisms (SNPs) throughout the SLC1A2 and SLC1A3 genes were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure frequencies by genotype. Multivariate Cox proportional hazards regression was used to estimate hazard ratios (HRs) for genotypes significant in Kaplan-Meier analyses. Thirty-nine tagging SNPs were examined (SLC1A2: n=21, SLC1A3: n=18). PTS developed in 57 (21.4%) individuals. Of those with PTS, n=20 (35.7%) had an immediate/early seizure within the first seven days, and n=36 (64.3%) had a late seizure occurring between eight days and three years post-TBI. When adjusting for multiple comparisons, rs4869682 genotypes (SLC1A3, GG vs. T-carriers) were associated with time to first seizure (p=0.003). Median time until first seizure was 20.4 days for individuals with a GG genotype and 44.8 days for T-carriers. After adjusting for covariates, rs4869682 GG-homozygotes had a 2.05 times increased PTS risk versus T-carriers (aHR=2.08, 95% confidence interval: 1.20, 3.62, p=0.009). Variation within SLC1A3 is associated with accelerated epileptogenesis and clinical PTS development after sTBI. Future studies should validate these findings and examine how genetic variation at rs4869682 may be a target for PTS prevention and treatment.