Sequence-independent effects of phosphorothiolated oligonucleotides on synaptic transmission and excitability in the hippocampus in vivo
Abstract
Antisense oligodeoxynucleotides (ODNs) have the potential to be a powerful tool for regulating gene expression and mRNA translation in spatially and temporally restricted domains. Prior to investigating the effects of antisense ODNs on hippocampal long-term potentiation, we investigated whether there are any non-specific effects of ODNs on perforant path synaptic transmission in the dentate gyrus of both pentobarbital-anaesthetized and awake, freely moving rats. Single injections of phosphorothioated antisense ODNs (4 nmol) to the immediate early gene zif/268 caused a rapid (within minutes) and long-lasting (>24 hr) profound depression of the perforant path evoked field potentials. This depressive effect was due to the phosphorothioate modification since a depression was not seen with unmodified antisense ODNs, relative to saline controls. Furthermore, the effect was not sequence-specific since modified 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 o...Continue Reading
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