Neuropeptides-immunoreactivity and their mRNA expression in kindling: functional implications for limbic epileptogenesis.

Abstract

Recent studies have demonstrated that neuropeptide expression in forebrain neurons is responsive to changes in physiological activity. This is particularly true in the hippocampus where the expression of various neuropeptides has been reported to change in distinct neuronal populations in response to seizure activity. The aim of this work is to review and integrated the information on the pathological changes and functional modifications in neuropeptide systems of the hippocampal formation in kindling and other models of limbic epilepsy. This will be done by presenting a study in which we investigated the changes in the expression of somatostatin, neuropeptide Y (NPY), neurokinin B (NKB) and cholecystokinin-octapeptide (CCK) in the rat hippocampal principal neurons during and after kindling of the hippocampus using immunocytochemistry and in situ hybridization analysis of mRNA. NPY-IR was transiently expressed in the granule cells/mossy fibres after the preconvulsive stage 2 and 2 days but not 1 week after three consecutive tonic-clonic seizures (stage 5). A more pronounced increase was observed in NKB-IR lasting 1 week after kindling acquisition. Only the NKB mRNA expression was enhanced in granule cells at these intervals. At stages 2 and 5, somatostatin- and NPY-IR and their mRNA levels were markedly increased in interneurons in the deep hilus and in the polymorphic cell layer and their presumed projections to the outer molecular layer of the dentate gyrus. NKB- and CCK-IR and their mRNAs were highly expressed in basket cells at both stages of kindling. Their IR was increased in the inner molecular layer of the dentate gyrus in the ventral hippocampus. Peptide-containing neurons in the hilus appeared well preserved in spite of a reduction of Nissl stained cells by 24 % in the stimulated and contralateral hippocampus at stage 5. In the hippocampus proper, somatostatin and NPY-IR were enhanced in the stratum lacunosum molecular while CCK-IR fibres and its mRNA were particularly expressed in the pyramidal cell layer. The number of Somatostatin-, NKB- and CCK-IR cells was increased in the subiculum. The intensity of these changes was similar 2 days after stages 2 or 5 of kindling. Less pronounced effects were observed 1 week after kindling completion. These results, in the frame of the literature data, suggest that lasting functional changes occur in distinct neuropeptide-containing neurons during limbic epileptogenesis. This may have profound effects on synaptic transmission and contribute to modulate hippocampal excitability.