Abstract
Signaling between neurons and glia is necessary for the formation of functional neural circuits. A role for microglia in the maturation of connections in the medial nucleus of the trapezoid body (MNTB was previously demonstrated by postnatal microglial elimination using a colony stimulating factor 1 receptor (CSF1R). Defective pruning of calyces of Held and significant reduction of the mature astrocyte marker glial fibrillary acidic protein (GFAP) were observed after hearing onset. Here, we investigated the time course required for microglia to populate the mouse MNTB after cessation of CSF1R inhibitor treatment. We then examined whether defects seen after microglial depletion were rectified by microglial repopulation. We found that microglia returned to control levels at 4 weeks (wk) of age (18 days post cessation of treatment). Calyceal innervation of MNTB neurons was comparable to control levels at 4 wk, and GFAP expression recovered by 7 wk. We further investigated the effects of microglia elimination and repopulation on auditory function using auditory brainstem recordings (ABR). Temporary microglial depletion significantly elevated auditory thresholds in response to 4. 8, and 12 kHz at 4 wk. Treatment significantly affected latencies, interpeak latencies, and amplitudes of all the ABR peaks in response to many of the frequencies tested. These effects largely recovered by 7 wk. These findings highlight the functions of microglia in the formation of auditory neural circuits early in development. Further, the results suggest that microglia retain their developmental functions beyond the period of circuit refinement.
Significance Statement Auditory brainstem pathways are optimized for their special functions that are shaped during development, which rely on the functions of non-neuronal cells, such as microglia and astrocytes. When microglia were pharmacologically eliminated during the early postnatal period with a CSF1R inhibitor, excess calyces were not pruned and astrocytes did not mature properly in the auditory brainstem. Here we show that once this drug is withdrawn, microglia gradually return to the auditory nuclei. After microglia re-emerge in the MNTB, synaptic pruning of calyces of Held resumes and maturation of astrocytes and auditory function recover. The findings suggest that the auditory brainstem pathways can be shaped by microglia even after their normal period of circuit development.
Footnotes
Authors report no conflict of interest.
This work was supported by NIH R01 DC010796, R01NS083801 (NINDS), R01AG056768 (NIA). This study was made possible in part through access to the Optical Biology Core Facility of the Developmental Biology Center, a shared resource supported by the Cancer Center Support Grant (CA-62203) and Center for Complex Biological Systems Support Grant (GM-076516) at the University of California, Irvine.
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