Abstracts

Severe hypoglycemia is associated with neurological impairments, most frequently with seizures. The expression of hypoglycemic seizures is not well understood as depleting glucose generally leads to neuronal silencing and not to excessive synchronized discharges characteristic of seizures. Due to the high demand of neurons for glucose supply, the brain contains specialized glucosensing neurons to regulate glucose homeostasis. These neurons are changing their firing rate based on glucose levels. One of the regions, which neurons show an increase in firing rate with decreasing glucose levels is the substantia nigra pars reticulata (SNR), a structure critically involved in regulation of seizures. Thus, we investigated the role of the SNR GABAergic neurotansmission in hypoglycemic seizures. We used adult male rats. Hypoglycemic seizures were induced by systemic injection of insulin following bilateral infusion of muscimol or gabazine (GABA-A receptor agonist and antagonist, respectively) and baclofen or CGP 52432 (GABA-B receptor agonist and antagonist, respectively) in the SNR. Controls received saline infusions (the solvent). We measured the onset of hypoglycemic seizures. Cannula placements were confirmed histologically. Infusions of GABA receptor affecting agents in the SNR are accompanied by stereotypic behavior, sniffing, gnawing, rotation. The stereotypies were present during the entire experiment. The hypoglycemic seizures started as slow clonic movements of all four limbs and/or by barrel rotations. Infusions of muscimol of gabazine had no effect on the onset of hypoglycemic seizures. On the other hand, infusions of GABA-B receptor agents resulted in opposite effects: baclofen delayed and CGP 52432 accelerated the onset of hypoglycemic seizures. The data suggest that the nigral GABA-B but not GABA-A receptor system modulates the onset of hypoglycemic seizures. This may be due to receptor trafficking during severe hypoglycemia. It has been shown that GABA-A but not GABA-B receptors internalize during metabolic stress conditions. Our study brings new insights into understanding of mechanisms involved in generation of hypoglycemic seizures. (Supported by NS 20253 from the NIH, CURE Foundation and the Heffer Family Medical Foundation.)