Abstract
In the brain, fast wxcitatory synaptic transmission is mostly mediated by the alpha-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) subtype of the glutamate receptors. Molecular cloning has revealed that four subunits, GluR1, GluR2, GluR3, and GluR4 form heteromeric receptors with high affinity for AMPA. Because antagonists and agonists do not discriminate between individual AMPA receptor subunits, we decided to use antisense oligonucleotides to block the expression of the GluR2 subunit within the receptor complex in adult animals. In the present study, we exploited several advantages afforded by the guinea pig cochlea to determine whether an antisense oligonucleotide directed to the mRNA of the GluR2 subunit could modify primary auditory neurotransmission. While a random probe with the same base composition had no effect, a GluR2 antisense oligonucleotide, continuously delivered into the cochlea, transiently reduced the compound action potential and diminished spontaneous activity of single auditory nerve fibers. Although antisense oligonucleotides penetrated a variety of cells, their effect could be physiologically localized to a single site of GluR2 antisense probe action, the primary auditory neuron. Subunit specif...Continue Reading
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