| Description |
Epilepsy is a chronic neurological disorder characterized by the presence of unprovoked, recurrent, spontaneous seizures. The GABA hypothesis of epilepsy states that a decrease in GABAergic tone leads to an imbalance between excitatory and inhibitory transmission and increases seizure susceptibility. The extracellular levels of GABA are controlled by the GABA transporters (GATs), including the betaine/GABA transporter (BGT1). BGT1 transports both GABA and the organic osmolyte, betaine. Inhibitory tone and osmotic balance both play roles in controlling neuronal excitability, making BGT1 a potential target for the modulation of excitability. Recently, studies utilizing an equipotent inhibitor of GAT1 and BGT1, EF1502, and TGB, a GAT1 selective inhibitor, suggested that BGT1 inhibition is anticonvulsant. Seizures, pain, anxiety, depression, and other neuropsychiatric disorders are influenced by the GABAergic system, including modulation by GAT activity. However, little is known about the involvement of BGT1. Since BGT1 may be involved in the control of osmotic balance and extracellular GABA levels, it has the potential to be involved in the modulation of these disorders. The current dissertation was designed to test the hypothesis that BGT1 expression plays a role in epilepsy, seizure susceptibility, and other neurological disorders, including depression, anxiety, pain, and cognition, as well as motor function. iv To test the hypothesis that BGT1 expression is involved in epilepsy, a model of temporal lobe epilepsy, i.e., status epilepticus (SE), was utilized and BGT1 mRNA expression determined at several time-points following SE. BGT1 mRNA expression was compared to that of the other GATs and osmoprotective genes. From these studies, it appears that the expression of BGT1 may be involved in the pathogenesis of epilepsy. To test whether BGT1 is involved in the regulation of acute seizure susceptibility, four models of seizure threshold were utilized in BGT1 KO and WT mice (minimal tonic extension, minimal clonic, 6 Hz, and i.v.PTZ seizure threshold tests). Furthermore, the rate of corneal kindling acquisition was ascertained. No differences in seizure threshold were observed between genotypes. However, BGT1 KO mice displayed a behavioral profile distinct from that of their WT littermate controls. BGT1 KO mice have increased depressive and anxiety-like behaviors as well as a ‘manic' phenotype. The results from this dissertation provide evidence in support of continued investigation of BGT1 in a number of distinct CNS disorders. |
