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Published on: May 10, 2019
Long-term microglia depletion impairs synapse elimination and auditory brainstem function
Sima M Chokr1, Giedre Milinkeviciute1, Gisselle A Jimenez1
1Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, 92697, USA.
Abstract:
Specialized sound localization circuit development requires synapse strengthening, refinement, and pruning. Many of these functions are carried out by microglia, immune cells that aid in regulating neurogenesis, synaptogenesis, apoptosis, and synaptic removal. We previously showed that postnatal treatment with BLZ945 (BLZ), an inhibitor of colony stimulating factor 1 receptor (CSF1R), eliminates microglia in the brainstem and disables calyceal pruning and maturation of astrocytes in the medial nucleus of the trapezoid body (MNTB). BLZ treatment results in elevated hearing thresholds and delayed signal propagation as measured by auditory brainstem responses (ABR). However, when microglia repopulate the brain following the cessation of BLZ, most of the deficits are repaired. It is unknown whether this recovery is achievable without the return of microglia. Here, we induced sustained microglial elimination with a two-drug approach using BLZ and PLX5622 (PLX). We found that BLZ/PLX treated mice had impaired calyceal pruning, diminished astrocytic GFAP in the lateral, low frequency, region of MNTB, and elevated glycine transporter 2 (GLYT2) levels. BLZ/PLX treated mice had elevated hearing thresholds, diminished peak amplitudes, and altered latencies and inter-peak latencies. These findings suggest that microglia are required to repopulate the brain in order to rectify deficits from their ablation.
Insights
Microglia are essential immune cells for brain development. Sustained elimination of microglia impairs sound localization circuits, indicating their crucial role in repairing developmental deficits.
Area of Science:
- Neuroscience
- Immunology
- Auditory System Development
Background:
- Microglia, brain immune cells, regulate synaptic development and pruning essential for auditory circuit formation.
- Previous studies showed postnatal inhibition of colony stimulating factor 1 receptor (CSF1R) with BLZ945 (BLZ) eliminates microglia, impairing calyceal pruning and auditory function.
- Recovery of auditory function was observed upon microglia repopulation after BLZ cessation, but the necessity of this repopulation for repair remained unclear.
Purpose of the Study:
- To investigate if auditory circuit deficits caused by microglial ablation can be repaired without microglia repopulation.
- To examine the effects of sustained microglial elimination using a dual-drug approach (BLZ945 and PLX5622) on auditory development and function.
Main Methods:
- Sustained microglial elimination was induced in mice using a combination of BLZ945 (BLZ) and PLX5622 (PLX).
- Auditory brainstem responses (ABR) were measured to assess hearing thresholds, signal propagation, and other auditory parameters.
- Histological analyses were performed to evaluate calyceal pruning, astrocyte maturation (GFAP expression), and glycine transporter 2 (GLYT2) levels in the medial nucleus of the trapezoid body (MNTB).
Main Results:
- Sustained microglial elimination with BLZ/PLX resulted in impaired calyceal pruning and reduced astrocytic GFAP in the low-frequency MNTB region.
- Elevated glycine transporter 2 (GLYT2) levels were observed in BLZ/PLX treated mice.
- BLZ/PLX treatment led to elevated hearing thresholds, diminished peak amplitudes, and altered latencies in auditory brainstem responses.
Conclusions:
- Sustained microglial elimination disrupts critical developmental processes in the auditory pathway, including calyceal pruning and astrocyte maturation.
- The observed auditory deficits suggest that microglia are necessary for the proper development and function of sound localization circuits.
- These findings underscore the essential role of microglia in repairing developmental deficits within the auditory system, highlighting that their return is likely required for functional recovery.
