Intrahippocampal infusion of antisense oligodeoxynucleotide to the GABA(A)receptor gamma 2 subunit enhances neuropeptide Y gene expression

The effects of hippocampal treatment with a phosphorothioate oligodeoxynucl eotide (ODN) antisense to the gamma -aminobutyric acid (GABA)(A) receptor g amma2 subunit on neuropeptide Y (NPY) were studied. Adult male Wistar rats were treated with unilateral intrahippocampal infusion of gamma2 subunit an tisense ODN for 5 days. Rats infused with mismatch ODN and naive rats serve d as controls. Brain sections were analysed for levels of NPY mRNA by in si tu hybridisation, NPY-immunoreactivity (NPY-ir) by means of immunocytochemi stry, and specific NPY binding sites by in vitro receptor autoradiography. Following infusion of antisense ODN, a marked increase in cytoplasmic NPY-i r was observed in hilar neurones of the fascia dentata, Further, intense NP Y-ir was visualised in the mossy fibres and in cell bodies of the entorhina l cortex and throughout the neocortex. High levels of NPY mRNA were detecte d in the same cortical areas of antisense treated rats. A very large increa se was observed in the piriform and parietal areas. NPY gene expression als o occurred in the granular cell layer, in which no NPY mRNA could be detect ed in normal animals. The level and distribution of cells displaying high l evels of NPY mRNA differed among animals, perhaps as a result of the distin ct anatomical location of ODN infusion. Finally, hippocampal levels of NPY specific binding increased, suggesting that NPY neurotransmission is marked ly increased. These findings are reminiscent of reported changes in the exp ression of NPY mRNA and immunoreactivity in conditions of increased neurona l excitation and support the usefulness of the present animal model for the study of epileptic phenomena. (C) 2001 Elsevier Science Inc.