Reactive Neurogenesis and Down-Regulation of the Potassium-Chloride Cotransporter KCC2 in the Cochlear Nuclei after Cochlear Deafferentation.

Brahim Tighilet,Marina I Siponen,Arnaud J Noreña,Sophie Dutheil

doi:10.3389/fphar.2016.00281

Abstract

While many studies have been devoted to investigating the homeostatic plasticity triggered by cochlear hearing loss, the cellular and molecular mechanisms involved in these central changes remain elusive. In the present study, we investigated the possibility of reactive neurogenesis after unilateral cochlear nerve section in the cochlear nucleus (CN) of cats. We found a strong cell proliferation in all the CN sub-divisions ipsilateral to the lesion. Most of the newly generated cells survive up to 1 month after cochlear deafferentation in all cochlear nuclei (except the dorsal CN) and give rise to a variety of cell types, i.e., microglial cells, astrocytes, and neurons. Interestingly, many of the newborn neurons had an inhibitory (GABAergic) phenotype. This result is intriguing since sensory deafferentation is usually accompanied by enhanced excitation, consistent with a reduction in central inhibition. The membrane potential effect of GABA depends, however, on the intra-cellular chloride concentration, which is maintained at low levels in adults by the potassium chloride co-transporter KCC2. The KCC2 density on the plasma membrane of neurons was then assessed after cochlear deafferentation in the cochlear nuclei ipsilateral and contralateral to the lesion. Cochlear deafferentation is accompanied by a strong down-regulation of KCC2 ipsilateral to the lesion at 3 and 30 days post-lesion. This study suggests that reactive neurogenesis and down-regulation of KCC2 is part of the vast repertoire involved in homeostatic plasticity triggered by hearing loss. These central changes may also play a role in the generation of tinnitus and hyperacusis.

Highlights

It has been suggested that homeostatic regulation applies to the averaged neural activity as many neural processes, such as long-term potentiation and depression, can produce unstable activity, i.e., runaway activity or no activity at all, respectively (Davis and Goodman, 1998; Turrigiano and Nelson, 1998; Turrigiano et al, 1998)
In the unilateral cochlear neurectomy (UCN) group of cats, bromo-2 deoxyuridine (BrdU)-Ir cells were exclusively restricted to the deafferented cochlear nucleus (CN)
The quantitative analysis showed a significantly increased number of BrdU-Ir nuclei by the first day and peaked at 3 days after UCN for the four main CN sub-divisions (+1382% in the CGL, +2140.93% in the AVCN, +2252.07% in the PVCN, and +2667.03% in the DCN compared to controls, P < 0.0001)

Summary

Introduction

It has been suggested that homeostatic regulation applies to the averaged neural activity as many neural processes, such as long-term potentiation and depression, can produce unstable activity, i.e., runaway activity or no activity at all, respectively (Davis and Goodman, 1998; Turrigiano and Nelson, 1998; Turrigiano et al, 1998). The repertoire of cellular and molecular mechanisms involved in homeostatic plasticity is considerable (Burrone and Murthy, 2003; Turrigiano and Nelson, 2004; Davis, 2006; Turrigiano, 2008; Watt and Desai, 2010). Many of the newborn neurons following the deafferentation were of GABAergic phenotype (Tighilet et al, 2007; Dutheil et al, 2013) At first sight, this result is surprising as sensory deafferentation is usually followed by neural hyperexcitability (Noreña et al, 2003; Sumner et al, 2005; Mulders and Robertson, 2009; Kalappa et al, 2014), consistent with a reduction of inhibitory neurotransmission (Suneja et al, 1998; Milbrandt et al, 2000; Argence et al, 2006). A down-regulation of KCC2 after various manipulations have been shown to make the polarity of GABA depolarizing (Coull et al, 2003; Boulenguez et al, 2010)

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