Elucidation of changes in the expression of mRNAs of peptides during amygdala kindling is a project focus. Neuropeptides are important modulators of excitatory and inhibitory neurotransmitters and may have pro- and/or anticonvulsant properties. Following kindled seizures, the expression of peptide mRNAs (e.g., thyrotropin-releasing hormone [TRH], neuropeptide Y [NPY], enkephalin [ENK], and dynorphin) may increase or decrease, depending on the peptide, in limbic areas known to be important in seizures. Expression is also altered in different brain regions at different times: TRH and NPY mRNAs are increased in the dentate gyrus 4 hrs after a seizure whereas at 24 hrs after a seizure the levels are increased in the limbic cortices, but have returned to pre- seizure levels in the dentate gyrus. Each neuropeptide has its unique pattern of activation or inhibition, suggesting that each plays a different role in the kindling process. A unique and significant alteration of peptide mRNAs (particularly of TRH mRNA) with contingent tolerance to carbamazepine (CBZ) has been found. In rats that are tolerant to the anticonvulsant effects of CBZ, the TRH mRNA increases usually found following a seizure are not seen. These studies suggest that TRH and other peptides may be functionally important for CBZ's anticonvulsant properties. Previous studies showed that Fos and TRH mRNA were co-localized in limbic system cells following kindling. To further understand the regulation of kindled-induced neuropeptide mRNA alterations, studies on the regulation of TRH mRNA by thyroid hormone were conducted. Hypo- and hyperthyroidism, respectively, increased and decreased hypothalamic TRH mRNA and pituitary TSH mRNA, while leaving kindling-induced increases in limbic structures unaffected. However, the kindling-induced decrease in hippocampal neurotrophin-3 (NT-3) was reversed in hypothyroid rats. This suggests that while the limbic TRH mRNA system is independent of thyroid hormone function, kindling-induced alteration in limbic system trophic factors may be regulated by thyroid hormone.
