MOLECULAR BIOLOGIC BASIS OF KINDLING

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Previous work from our laboratory has demonstrated a time dependent change in the levels of somatostatin in the cortex and hippocampus of the kindled rat brain. In addition, the activity of tyrosine hydroxylase is increased immediately following a seizure. Glutamate decarboxylase levels were not found to be changed in any stage of the kindled rat brain. In view of the fact that some regulatory DNA such as c-fos are altered in the seizure state, it was of interest to undertake a study of the expression of the mRNA for somatostatin, tyrosine hydroxylase and glutamine decarboxylase and their correlation with the expression of the c-fos gene to determine if c-fos regulates the levels of expression of the above- mentioned compounds. Currently the above studies are being expanded to incorporate the time course of the development of mRNA alterations and additional investigations of blocking of seizures on the expression of the mRNA are being undertaken. Long-term studies include in situ hybridization studies of the human epileptic focus and comparing it to the nonfocal tissue from the same patient. These studies will help determine the phase of the seizure progression when the mRNA changes occur. Such observations will help understand how the expression of genes is influenced in the situation where increased spiking activity occurs in the brain. Such an understanding of the kindled brain may help in elucidating the long-term changes which occur in the human epileptic focus. Similarly studies are ongoing to correlate the changes in amino acid transmitters, neuropeptides, enzymes and receptors with the development of seizures.