Abstracts

Rationale: While the ionotropic glutamate receptors (iGluRs) have been extensively studied, little is known about the role of metabotropic glutamate receptors (mGluRs) in seizure generation and epileptogenesis associated with altered brain development, including Tuberous Sclerosis Complex (TSC) and focal cortical dysplasia (FCD). Animal model studies show that Group I mGluRs, including mGluR1 and mGluR5, are pro-convulsive, while specific mGluR antagonists are effective in suppressing seizure activity. Furthermore, experimental deletion of Tsc1 impairs mGluR-dependent long-term depression. We hypothesized that Group I mGluRs are expressed at higher levels in TSC and FCD compared to controls, which may significantly contribute to altered synaptic function, network excitability and information processing in these patients. Methods: Cortical samples from TSC (n= 5; ages 0.9-5 years) and non-TSC epilepsy patients (n=5; ages 21.5-37 years) were obtained during brain surgery for treatment of pharmaco-resistant epilepsy at NYU Langone Medical Center. The cases were further diagnosed as either TSC or FCD Type Ia by standard neuropathological examination. Age-matched and region-matched control specimens from cases with normal neurological history (n=6; ages 2-24 years) were obtained from University of Maryland Brain and Tissue Bank. The study was approved by the local Institutional Review Board. Frozen cortical samples were used to separate the membrane fraction and blots were probed for mGluR1 (1:1000) and mGluR5 (1:1000). Mean expression levels were compared among groups and statistical significance (p<0.05) was established using two-tailed t-tests.Results: mGluR1 expression was significantly upregulated relative to controls in both TSC (270 40% of control; p<0.05) and FCD cortex (136 10% of control; p<0.05), with higher levels in TSC relative to FCD (p<0.05). mGluR5 was also significantly elevated in TSC (370 34% of control; p<0.01) and FCD (321 25% of control; p<0.001), with no significant difference between groups. In TSC, altered mGluR expression extended into the epileptogenic, normal appearing peri-tuberal cortex (177 31% of control, p>0.05 for mGluR1 and 256 15% of control, p<0.01 for mGluR5).Conclusions: We demonstrate increased mGluR1 and mGluR5 expression in TSC and FCD cortex, which suggests that pharmacological manipulation of Group I mGluRs may represent a viable therapeutic approach for ameliorating chronic epilepsy in these patients, with possible fewer side effects compared to iGluR antagonists. In addition, our results may justify the use of selective mGluR positron emission tomography tracers to evaluate mGluR function in vivo, in order to better delineate the epileptogenic areas prior to surgery, or establish the optimal therapeutic window for agents directed targeting mGluRs. Supported by: FACES, TS Alliance and NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD, contract HHSN275200900011C.