Inhibition of hippocampal kindling by metabotropic glutamate receptor antisense oligonucleotides

Recent work has shown that metabotropic glutamate receptors (mGluRs) increa se in response to seizure activity and can contribute significantly to the expression and progression of partial seizures. Using the kindling model of temporal lobe seizures, we evaluated the ability of local hippocampal inje ctions of mGluR1 antisense or mGluR3 antisense oligonucleotides to suppress receptor expression and alter hippocampal kindling. Daily antisense inject ions in the hippocampus resulted in a significant decrease in mGluR1 or mGl uR2/3 immunoreactivity. Rats injected with mGluR3 antisense showed a brief suppression of afterdischarge duration when compared to matched rats inject ed with a nonsense-oligonucleotide. Rats injected with a mGluR1 antisense o ligonucleotide had a dramatic suppression of the rate of seizure progressio n with no significant effect on afterdischarge duration. Suppression of mGl uR1 synthesis by local antisense inhibition may provide a new therapeutic a pproach for the control of epileptogenesis.