-Original-

Role of Extracellular Signal-Regulated Kinase 2 in the Etiology of Tinnitus Caused by Moderate Noise Overexposure in Mice

Hirotaka Suzuki^1,2,*, Takeshi Matsunobu^1,2,*, Takaomi Kurioka³, Masato Fujioka^2,4,5, Shogo Endo⁶, Yasushi Satoh⁷ and Kimihiro Okubo¹

¹Department of Otorhinolaryngology-Head and Neck Surgery, Nippon Medical School, Tokyo, Japan
²Department of Otolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan
³Department of Otolaryngology, National Defense Medical College, Saitama, Japan
⁴Department of Molecular Genetics, Kitasato University School of Medicine, Kanagawa, Japan
⁵Molecular Genetics Unit, Kitasato University Graduate School of Medical Science, Kanagawa, Japan
⁶Aging Neuroscience Research Team, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
⁷Department of Biochemistry, National Defense Medical College, Saitama, Japan
^*Contributed equally

Background: Acoustic trauma is a common cause of acute sensorineural hearing loss associated with tinnitus; however, the underlying molecular mechanisms remain unclear. Extracellular signal-regulated kinase 2 (ERK2), a member of the mitogen-activated protein kinase family, is crucial in cellular signaling, especially in the nervous system, where it helps regulate neuroprotection, neurogenesis, and neuronal plasticity. ERK2 is activated in the cochlea by acoustic stimuli and plays a protective role in cochlear hair cells (HCs), which are the primary sensory receptors for hearing. However, the significance of ERK2 expression in HCs associated with development and etiology of tinnitus is largely unexplored.
Methods: To investigate the role of ERK2 in tinnitus development, the gap detection test (GAP) was used to evaluate HC-specific ERK2-conditional knockout mice (HC-E2CKO) exposed to moderate acoustic stimuli.
Results: Both control and HC-E2CKO mice showed normal prepulse inhibition levels (<0.6) before and after auditory damage, indicating normal functioning of sensorimotor gating pathways, excluding gross sensorimotor deficits. This confirmed that the animals were eligible for the GAP. HC-E2CKO mice showed a transient increase in the GAP ratio, indicating tinnitus development, 1 week after noise exposure, although the hearing threshold was not significantly elevated. The GAP ratio returned to normal after 2 weeks. In contrast, control mice did not exhibit elevation in hearing threshold and the GAP ratio remained normal.
Conclusion: Our findings suggest that ERK2 in the inner ear plays a role in tinnitus onset or perception after acoustic stress, potentially through inhibitory mechanisms.

J Nippon Med Sch 2025; 92: 253-261

Keywords
extracellular signal-regulated kinase 2, inner ear, acoustic trauma, tinnitus, gap detection test

Correspondence to
Takeshi Matsunobu, Department of Otorhinolaryngology-Head and Neck Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
t-matsunobu@nms.ac.jp

Received, November 21, 2024
Accepted, January 15, 2025