INHIBITION OF GLUTAMATE-INDUCED NEUROTOXICITY BY A TAU ANTISENSE OLIGONUCLEOTIDE IN PRIMARY CULTURE OF RAT CEREBELLAR GRANULE CELLS

Short-term exposure of primary cultures of cerebellar granule cells fr om neonatal rat brain to high concentrations of glutamate resulted in a significant increase of both immunoreactivity to and mRNA levels of tau protein. Timecourse experiments revealed the increases of tau immu noreactivity and mRNA levels to be maximal 2 h after the glutamate pul se. To investigate the relationship between newly synthesized tau prot ein and glutamate-induced neurotoxicity, neurons were preincubated wit h a specific tau antisense oligonucleotide. This treatment resulted in (i) inhibition of the glutamate-induced increase of tau immunoreactiv ity and (ii) a decrease in the sensitivity of the neurons to neurotoxi c concentrations of glutamate. These data indicate that induction of t he cytoskeleton-associated tau protein participates in the cascade of events promoted by glutamate leading to neurodegeneration.