Astrocyte Hypertrophy and Microglia Activation in the Rat Auditory Midbrain Is Induced by Electrical Intracochlear Stimulation.

Nicole Rosskothen-Kuhl,Ralf Birkenhäger,Robert-Benjamin Illing,Heika Hildebrandt

doi:10.3389/fncel.2018.00043

Nicole Rosskothen-Kuhl, Ralf Birkenhäger + Show 2 more

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https://doi.org/10.3389/fncel.2018.00043

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Abstract

Neuron–glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron–glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation.

Highlights

In the mammalian brain, any pattern of signaling activity is molding the substrate that carries it
The responses consisted of a widespread and massive instead of a focal expression of Fos in neurons (Figure 2B, arrowheads), the emergence of a densely aggregated astrocytes as revealed by GFAP staining (Figure 2D, arrowheads), and a marked change in the morphology of microglia indicated by IBA1 immunoreactivity indicating their transformation in an activated state (Figure 2F, arrowheads)
We show that this response is unrelated to neuronal or glial apoptosis. For reasons of their local specificity and their temporal order with respect to the quick emergence of Fos in neurons and the slow increase of GAD65/67 staining, the observed glioplastic response is suggestive of forming a link of molecular signaling and cellular remodeling between neuronal spiking activity and the reactive local strengthening of inhibitory circuits that have remained immature

Summary

Introduction

Any pattern of signaling activity is molding the substrate that carries it. One of the first indicators of reactive cellular modification due to neural network activity is the expression of the FBJ osteosarcoma oncogene fos, known as c-fos, in all parts of the mammalian central nervous system. Fos is often just used as a marker for spiking intensity indicating neuronal activity (Cohen and Greenberg, 2008; Cruz et al, 2013), but its deeper involvement is gradually acknowledged. As a monomer of the heterodimeric Fos:Jun activator protein-1 (AP-1) transcription factor, Fos may trigger the expression of specific genes that contribute to functional and structural alterations of the affected neurons and their surroundings. If no Fos is available, AP-1 rather comes in the pATF2:Jun variant, which activates a different set of genes (Rauch et al, 2016)

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