Altered vesicular glutamate transporter distributions in the mouse cochlear nucleus following cochlear insult

Abstract

Vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) have distinct distributions in the cochlear nucleus that correspond to the sources of the labeled terminals. VGLUT1 is mainly associated with terminals of auditory nerve fibers, whereas VGLUT2 is mainly associated with glutamatergic terminals deriving from other sources that project to the cochlear nucleus (CN), including somatosensory and vestibular terminals. Previous studies in guinea pig have shown that cochlear damage results in a decrease of VGLUT1-labeled puncta and an increase in VGLUT2-labeled puncta. This indicates cross-modal compensation that is of potential importance in somatic tinnitus. To examine whether this effect is consistent across species and to provide a background for future studies, using transgenesis, the current study examines VGLUT expression profiles upon cochlear insult by intracochlear kanamycin injections in the mouse. Intracochlear kanamycin injections abolished ipsilateral ABR responses in all animals and reduced ipsilateral spiral ganglion neuron densities in animals that were sacrificed after four weeks, but not in animals that were sacrificed after three weeks. In all unilaterally deafened animals, VGLUT1 density was decreased in CN regions that receive auditory nerve fiber terminals, i.e. in the deep layer of the dorsal cochlear nucleus (DCN), in the interstitial region where the auditory nerve enters the CN, and in the magnocellular region of the antero- and posteroventral CN. In contrast, density of VGLUT2 expression was upregulated in the fusiform cell layer of the DCN and in the granule cell lamina, which are known to receive somatosensory and vestibular terminals. These results show that a cochlear insult induces cross-modal compensation in the cochlear nucleus of the mouse, confirming previous findings in guinea pig, and that these changes are not dependent on the occurrence of spiral ganglion neuron degeneration.

Selective hair cell ablation and noise exposure lead to different patterns of changes in the cochlea and the cochlear nucleus

“…Previous studies have demonstrated loss of auditory nerve inputs in the VCN after acoustic overexposure (Kim et al, 2004), surgical destruction of the cochlea (Fyk-Kolodziej et al, 2011), and application of ototoxic substances (Zeng et al, 2009, Yuan et al, 2014, Heeringa et al, 2016), but the effects of other types of HC loss on the VCN are not well characterized. To evaluate stereological changes in the VCN after DT-induced HC loss, we prepared transverse sections (N = 6 animals for each group) stained with cresyl violet and assessed the total volume, neuron density, and cell size in the VCN (Fig.…”

“…VGLUT1 immunocytochemistry and quantification were conducted as described previously (Zhou et al, 2007, Heeringa et al, 2016). Sections were incubated for 30 minutes in a blocking solution containing 1% normal goat serum in PBS with 0.3% Triton X-100 followed by overnight incubation with primary antibody, anti-VGLUT1 (rabbit anti-VGLUT-1, Synaptic Systems, Germany), diluted in blocking solution 1:2000 for 18 hours at RT.…”

“…Synaptic degeneration, including decreases in GluR2 and VGLUT-1, and demyelination of auditory nerve fibers (ANFs) after cochlear insults have been reported (Zhou et al, 2007, Zeng et al, 2009, Barker et al, 2012, Tagoe et al, 2014, Wan et al, 2014, Heeringa et al, 2016). These studies used either noise or ototoxic drugs to induce cochlear damage.…”

Maladaptive plasticity in tinnitus — triggers, mechanisms and treatment

“…This effect is a consequence of an increase in glutamatergic neurotransmission from somatosensory fibers following loss of input from auditory pathways [102]. Interestingly, the upregulation of glutamatergic inputs from the somatosensory system occurs after a ‘threshold’ level of cochlear damage, beyond which, no further changes occur [103]. Tinnitus-related changes in auditory-somatosensory integration by the fusiform cells include increased long-term potentiation [41], likely mediated by the increased non-auditory glutamatergic innervation after cochlear damage [75, 76].…”

Gαi Proteins are Indispensable for Hearing

“…For the auditory system, it was shown that the peripheral loss of response to sensory stimuli due to traumatic events, aging processes or genetic defects among others triggers central gain adjustment in order to re-stabilize the network through a disproportional elevation of the neuronal firing rate [31,82,83]. How target neurons of auditory nerve fibers, likely to be present in the dorsal [59] [85] may participate in generation of compensating central hyperactivity. Indeed, Gα-Gβγ signaling has been shown to modulate basic G proteinactivated K + -channel GIRK [86] in response to e.g.…”