Midazolam reverses salicylate-induced changes in brain-derived neurotrophic factor and arg3.1 expression: implications for tinnitus perception and auditory plasticity.
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 GABA(A) 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.
Department of Otorhinolaryngology, Universität Tübingen, Tübingen, Germany.
Rama
R
Panford-Walsh
Wibke
W
Singer
Lukas
L
Rüttiger
Saida
S
Hadjab
Justin
J
Tan
Hyun-Soon
HS
Geisler
Ulrike
U
Zimmermann
Iris
I
Köpschall
Karin
K
Rohbock
Anna
A
Vieljans
Elmar
E
Oestreicher
Marlies
M
Knipper
D000818:Animals; D001303:Auditory Cortex / Q000187:drug effects / Q000378:metabolism; D001306:Auditory Pathways / Q000187:drug effects / Q000378:metabolism; D001307:Auditory Perception / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D034381:Hearing Loss / Q000139:chemically induced; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000378:metabolism; D012459:Salicylates / Q000008:administration & dosage / Q000494:pharmacology*; D014012:Tinnitus / Q000378:metabolism* / Q000473:pathology
D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018079:Receptors, GABA; D012459:Salicylates; C092069:activity regulated cytoskeletal-associated protein; D008874:Midazolam