SEQUENCE-INDEPENDENT EFFECTS OF PHOSPHOROTHIOATED OLIGONUCLEOTIDES ONSYNAPTIC TRANSMISSION AND EXCITABILITY IN THE HIPPOCAMPUS IN-VIVO

Antisense oligodeoxynucleotides (ODNs) have the potential to be a powe rful tool for regulating gene expression and mRNA translation in spati ally and temporally restricted domains. Prior to investigating the eff ects of antisense ODNs on hippocampal long-term potentiation, we inves tigated whether there are any nonspecific effects of ODNs on perforant path synaptic transmission in the dentate gyrus of both pentobarbital -anaesthetized and awake, freely moving rats. Single injections of pho sphorothioated antisense ODNs (4 nmol) to the immediate early gene zif /268 caused a rapid (within minutes) and long-lasting (> 24 hr) profou nd depression,of the perforant path evoked field potentials. This depr essive effect was due to the phosphorothioate modification since a dep ression was not seen with unmodified antisense ODNs, relative to salin e controls. Furthermore, the effect was not sequence-specific since mo dified sense ODNs caused the same degree of depression. The depression caused by the modified antisense ODNs was dose-dependent and specific to synaptic transmission, since antidromic population spikes elicited by mossy fibre stimulation were relatively unaffected compared to the orthodromic responses. A second unexpected side-effect of the modifie d ODNs was cellular hyperexcitability, such that bursts of epileptifor m spikes in the EEG occurred both spontaneously and as a result of syn aptic stimulation. While the mechanism of the synaptic depression rema ins unknown, these results indicate that phosphorothioate-modified ODN s exert profound non-specific effects on synaptic transmission in the hippocampus, that have the potential to seriously compromise any corre sponding behavioural or electrophysiological studies. (C) 1997 Publish ed by Elsevier Science Ltd.