Deafferentation-Induced Redistribution of MMP-2, but Not of MMP-9, Depends on the Emergence of GAP-43 Positive Axons in the Adult Rat Cochlear Nucleus

Fredrich, Michaela; Illing, Robert‐Benjamin

doi:10.1155/2011/859359

Cited by 4 publications

(10 citation statements)

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“…Upon unilateral SD of the auditory brainstem, regions rich in MMP2 locally correspond to regions rich in Gap43 (Fredrich & Illing, ). Moreover, changes of MMP2 expression after SD are conditional upon an effective re‐innervation revealed by Gap43 immunoreactivity (Fredrich & Illing, ). A release of MMP2 from astrocytes upon the approach of growing neurites and synaptogenesis locally and temporally coincides with the degradation of Ncan from PNNs in VCN.…”

Section: Discussionmentioning

confidence: 99%

Sensory deafferentation modulates and redistributes neurocan in the rat auditory brainstem

2019

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Introduction Cochlear ablation causing sensory deafferentation ( SD ) of the cochlear nucleus triggers complex re‐arrangements in the cellular and molecular communication networks of the adult mammalian central auditory system. Participation of the extracellular matrix (ECM) in these processes is not well understood. Methods We investigated consequences of unilateral SD for the expression and distribution of the chondroitin sulfate proteoglycans, neurocan (Ncan) and aggrecan (Agg), alongside various plasticity markers in the auditory brainstem of the adult rat using immunohistochemical techniques. Results In the deafferented ventral cochlear nucleus (VCN), Ncan expression increased massively within 3 postoperative days (POD), but rapidly decreased thereafter. Agg showed a similar but less pronounced progression. Decrease in Ncan was spatially and temporally related to the re‐innervation of VCN documented by the emergence of growth‐associated protein Gap43 contained in nerve fibers and presynaptic boutons. Concurrently, astrocytes grew and expressed matrix metalloproteinase‐2 (MMP2), an enzyme known to emerge only under re‐innervation of VCN. MMP2 is capable of cleaving both Ncan and Agg when released. A transient modulation of the ECM in the central inferior colliculus on the side opposite to SD occurred by POD1. Modulations of glutamatergic synapses and Gap43 expression were detected, reflecting state changes of the surrounding tissue induced by transsynaptic effects of SD . Conclusions The ECM variously participates in adaptive responses to sudden deafness by SD on several levels along the central auditory pathway, with a striking spatial and temporal relationship of Ncan modulation to astrocytic activation and to synaptogenesis.

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Section: Discussionmentioning

confidence: 99%

Sensory deafferentation modulates and redistributes neurocan in the rat auditory brainstem

2019

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“…In this case, the reduction in GAP‐43 immunoreactivity affected the entire AVCN, which is reflected by the lack of staining differences among AVCN subregions (Figs C and H, third bar). In some experiments, neuronal death was caused only in part of the VNTB, whereas neurons in other parts remained viable, owing to an off‐center KA injection (not illustrated) (Fredrich & Illing, ). In these cases, a patchy pattern of GAP‐43 staining emerged in the ipsilateral AVCN (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Nissl staining served to determine the success and degree of the resulting excitotoxic lesion. A total loss of neuronal somata in the VNTB (Figs C and D) indicated complete lesion of VNTB neurons (Fredrich & Illing, ).…”

Section: Resultsmentioning

confidence: 99%

“…Apparently, much of this increase resulted from an increase inside astrocytes, as the areal fraction of MMP‐9 or MMP‐2 co‐localisation with GFAP in the AVCN and the fraction of MMP‐9 or MMP‐2 inside the GFAP cytoskeleton increased strongly within this time frame (Figs E–H). In an earlier study (Fredrich & Illing, ), we showed that neurons of the sensory deafferented AVCN secrete MMP‐9 and MMP‐2, a process that might explain the changes in staining pattern after CA (Figs B and E).…”

Section: Discussionmentioning

confidence: 99%

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Differential molecular profiles of astrocytes in degeneration and re-innervation after sensory deafferentation of the adult rat cochlear nucleus

et al. 2013

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Ablating the cochlea causes total sensory deafferentation of the cochlear nucleus. Over the first postoperative week, degeneration of the auditory nerve and its synaptic terminals in the cochlear nucleus temporally overlaps with its re-innervation by axon collaterals of medial olivocochlear neurons. At the same time, astrocytes increase in size and density. We investigated the time courses of the expression of ezrin, polysialic acid, matrix metalloprotease-9 and matrix metalloprotease-2 within these astrocytes during the first week following cochlear ablation. All four proteins are known to participate in degeneration, regeneration, or both, following injury of the central nervous system. In a next step, stereotaxic injections of kainic acid were made into the ventral nucleus of the trapezoid body prior to cochlear ablation to destroy the neurons that re-innervate the deafferented cochlear nucleus by axon collaterals developing growth-associated protein 43 immunoreactivity. This experimental design allowed us to distinguish between molecular processes associated with degeneration and those associated with re-innervation. Under these conditions, astrocytic growth and proliferation showed an unchanged deafferentation-induced pattern. Similarly, the distribution and amount of ezrin and matrix metalloprotease-9 in astrocytes after cochlear ablation developed in the same way as under cochlear ablation alone. In sharp contrast, the astrocytic expression of polysialic acid and matrix metalloprotease-2 normally invoked by cochlear ablation collapsed when re-innervation of the cochlear nucleus was inhibited by lesioning medial olivocochlear neurons with kainic acid. In conclusion, re-innervation, including axonal growth and synaptogenesis, seems to prompt astrocytes to recompose their molecular profile, paving the way for tissue reorganisation after nerve degeneration and loss of synaptic contacts.

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“…These mice developed a degeneration of various inner ear structures including the loss of SGNs and degeneration of the organ of Corti as well as hearing loss. Cochlear ablation experiments in rats indicate that MMP-9 tends to be associated with neuropil reorganization related to fiber and terminal degeneration, whereas MMP-2 is predominantly involved in aiding reinnervation and synaptogenesis (Fredrich and Illing 2011). Interestingly, mice with hyperhomocysteinemia display an increase in cochlear expression of MMP-2 and MMP-9 (Kundu et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MMP-2 but not MMP-9 Influences Inner Ear Spiral Ganglion Neurons In Vitro

et al. 2014

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Matrix metalloproteinases (MMPs) play an important role in modeling of the extracellular matrix. There is increasing evidence that these proteases are important in neurite elongation and axonal guidance during development in the central nervous system and retina. Moreover, they are also expressed after acute injury and can be the key mediators of pathogenesis. However, the role of MMPs in the inner ear is largely unknown. Our group recently demonstrated that general inhibition of MMPs resulted in auditory hair cell loss in vitro. In the present study, we investigated the role of MMPs in inner ear spiral ganglion neuron (SGN) survival, neuritogenesis and neurite extension by blocking MMPs known to be involved in axonal guidance, neurite elongation, and apoptosis in other neuronal systems. Spiral ganglion (SG) explants from 5-day-old Wistar rats were treated with different concentrations of the general MMP inhibitor GM6001, a specific MMP-2 inhibitor, and a specific MMP-9 inhibitor, in vitro. The general inhibitor of MMPs and the specific inhibition of MMP-2 significantly reduced both the number of neurites that extended from SG explants, as well as the length of individual neurites. However, neither the general inhibitor of MMPs nor the specific inhibition of MMP-2 influenced SGN survival. Inhibition of MMP-9 had no influence on SGNs. The data suggest that MMPs, and more specifically MMP-2, influence the growth of developing afferent neurites in the mammalian inner ear in vivo.

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Deafferentation-Induced Redistribution of MMP-2, but Not of MMP-9, Depends on the Emergence of GAP-43 Positive Axons in the Adult Rat Cochlear Nucleus

Cited by 4 publications

References 58 publications

Sensory deafferentation modulates and redistributes neurocan in the rat auditory brainstem

Sensory deafferentation modulates and redistributes neurocan in the rat auditory brainstem

Differential molecular profiles of astrocytes in degeneration and re-innervation after sensory deafferentation of the adult rat cochlear nucleus

Inhibition of MMP-2 but not MMP-9 Influences Inner Ear Spiral Ganglion Neurons In Vitro

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