Noise Exposure Alters Glutamatergic and GABAergic Synaptic Connectivity in the Hippocampus and Its Relevance to Tinnitus

Abstract

Accumulating evidence implicates a role for brain structures outside the ascending auditory pathway in tinnitus, the phantom perception of sound. In addition to other factors such as age-dependent hearing loss, high-level sound exposure is a prominent cause of tinnitus. Here, we examined how noise exposure altered the distribution of excitatory and inhibitory synaptic inputs in the guinea pig hippocampus and determined whether these changes were associated with tinnitus. In experiment one, guinea pigs were overexposed to unilateral narrow-band noise (98 dB SPL, 2 h). Two weeks later, the density of excitatory (VGLUT-1/2) and inhibitory (VGAT) synaptic terminals in CA1, CA3, and dentate gyrus hippocampal subregions was assessed by immunohistochemistry. Overall, VGLUT-1 density primarily increased, while VGAT density decreased significantly in many regions. Then, to assess whether the noise-induced alterations were persistent and related to tinnitus, experiment two utilized a noise-exposure paradigm shown to induce tinnitus and assessed tinnitus development which was assessed using gap-prepulse inhibition of the acoustic startle (GPIAS). Twelve weeks after sound overexposure, changes in excitatory synaptic terminal density had largely recovered regardless of tinnitus status, but the recovery of GABAergic terminal density was dramatically different in animals expressing tinnitus relative to animals resistant to tinnitus. In resistant animals, inhibitory synapse density recovered to preexposure levels, but in animals expressing tinnitus, inhibitory synapse density remained chronically diminished. Taken together, our results suggest that noise exposure induces striking changes in the balance of excitatory and inhibitory synaptic inputs throughout the hippocampus and reveal a potential role for rebounding inhibition in the hippocampus as a protective factor leading to tinnitus resilience.

Hippocampal Transcriptome-Wide Association Study Reveals Correlations Between Impaired Glutamatergic Synapse Pathway and Age-Related Hearing Loss in BXD-Recombinant Inbred Mice

“…We identified that the hippocampal glutamatergic synapse pathway is associated with ARHL. This is consistent with previous reports wherein the glutamatergic synaptic connectivity in the hippocampus could be altered by noise exposure ( Zhang et al, 2021 ). Glutamate is the excitatory neurotransmitter at many synapses in the central nervous system and has been extensively studied in relation to cognition, particularly learning and memory.…”

The Effect of Noise Trauma and Deep Brain Stimulation of the Medial Geniculate Body on Tissue Activity in the Auditory Pathway

“…The hippocampus has been shown to expresses a higher level of Arc protein after acute noise trauma, which is critical to long-term potentiation and depression of synaptic transmission, and thus memory formation [ 43 ]. Specifically, reduced GABAergic synaptic densities and cholinergic inputs to the hippocampus were observed in noise-exposed animals that developed tinnitus-like behaviour compared to the controls [ 44 , 45 ].…”

Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity

“…Central maladaptive plastic changes in response to peripheral insult has become central dogma in the field of tinnitus ( Figure 7(6) ; Roberts et al, 2010 ; Langguth et al, 2013 ; Auerbach et al, 2014 ; Henton and Tzounopoulos, 2021 ). Data from animals and humans have found many unique but likely overlapping mechanisms to explain the neural plastic changes related to tinnitus which include: increases in spontaneous (non-sound evoked) firing rate neural activity ( Longenecker and Galazyuk, 2011 ; Berger et al, 2014 ; Galazyuk et al, 2019 ); increased incidence of neurons burst firing ( Ma et al, 2006 ; Bauer et al, 2008 ), increased or decreased neural synchrony ( Eggermont and Tass, 2015 ; Marks et al, 2018 ), thalamocortical dysrhythmia ( De Ridder et al, 2015 ), altered balance between excitatory and inhibitory neurotransmission ( Middleton et al, 2011 ; Llano et al, 2012 ; Ma et al, 2020 ; Zhang et al, 2021 ), cortical reorganization ( Engineer et al, 2011 ; Jeschke et al, 2021 ), and neural inflammation ( Fuentes-Santamaría et al, 2017 ; Wang et al, 2019 ; Deng et al, 2020 ). The mechanisms of hyperacusis are much less studied but are thought to have similar etiologies as tinnitus ( Auerbach et al, 2014 ).…”