RT Journal Article
SR Electronic
T1 Midazolam Reverses Salicylate-Induced Changes in Brain-Derived Neurotrophic Factor and Arg3.1 Expression: Implications for Tinnitus Perception and Auditory Plasticity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 595
OP 604
DO 10.1124/mol.108.046375
VO 74
IS 3
A1 Rama Panford-Walsh
A1 Wibke Singer
A1 Lukas Rüttiger
A1 Saida Hadjab
A1 Justin Tan
A1 Hyun-Soon Geisler
A1 Ulrike Zimmermann
A1 Iris Köpschall
A1 Karin Rohbock
A1 Anna Vieljans
A1 Elmar Oestreicher
A1 Marlies Knipper
YR 2008
UL http://molpharm.aspetjournals.org/content/74/3/595.abstract
AB Tinnitus is a phantom auditory perception, which can be induced via application of concentrated sodium salicylate, and is known to be associated with hearing loss and altered neuronal excitability in peripheral and central auditory neurons. The molecular features of this excitability, however, has been poorly characterized to date. Brain-derived neurotrophic factor (BDNF), the activity-dependent cytoskeletal protein (Arg3.1, also known as Arc), and c-Fos are known to be affected by changes in excitability and plasticity. Using reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemistry, the expression of these genes was monitored in the rat auditory system after local (cochlear) and systemic application of salicylate. Induction of tinnitus and hearing loss was verified in a behavioral model. Regardless of the mode of salicylate application, a common pattern became evident: 1) BDNF mRNA expression was increased in the spiral ganglion neurons of the cochlea; and 2) Arg3.1 expression was significantly reduced in the auditory cortex. Local application of the GABAA receptor modulator midazolam resulted in the reversal not only of salicylate-induced changes in cochlear BDNF expression, but also in cortical Arg3.1 expression, indicating that the tinnitus-associated changes in cochlear BDNF expression trigger the decline of cortical Arg3.1 expression. Furthermore, local midazolam application reduced tinnitus perception in the animal model. These findings support Arg3.1 and BDNF as markers for activity changes in the auditory system and suggest a role of GABAergic inhibition of cochlear neurons in the modulation of Arg3.1 plasticity changes in the auditory cortex and tinnitus perception.