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Auditory Brainstem Deficits from Early Treatment with a CSF1R Inhibitor Largely Recover with Microglial Repopulation
Giedre Milinkeviciute1, Sima M Chokr1, Karina S Cramer2
1Department of Neurobiology and Behavior, University of California, Irvine, CA 92697.
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 four weeks of age (18 d postcessation of treatment). Calyceal innervation of MNTB neurons was comparable to control levels at four weeks and GFAP expression recovered by seven weeks. We further investigated the effects of microglia elimination and repopulation on auditory function using auditory brainstem recordings (ABRs). Temporary microglial depletion significantly elevated auditory thresholds in response to 4. 8, and 12 kHz at four weeks. 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 seven weeks. 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.
Insights
Microglia are essential for auditory circuit development. Their temporary depletion in mice impaired hearing and neural connections, but function recovered after microglia repopulated the brain.
Area of Science:
- Neuroscience
- Developmental Biology
- Auditory System Research
Background:
- Microglia play a crucial role in neural circuit formation.
- Previous studies showed microglial elimination impairs auditory circuit maturation in the medial nucleus of the trapezoid body (MNTB).
- Defects included impaired pruning of calyces of Held and reduced glial fibrillary acidic protein (GFAP) expression.
Purpose of the Study:
- To determine the repopulation kinetics of microglia in the mouse MNTB after colony stimulating factor 1 receptor (CSF1R) inhibitor treatment cessation.
- To assess if microglial repopulation rescues the developmental defects observed after depletion.
- To investigate the impact of microglial depletion and repopulation on auditory function.
Main Methods:
- CSF1R inhibitor treatment was used for postnatal microglial depletion in mice.
- Microglial repopulation time course in the MNTB was monitored after treatment cessation.
- Calcular innervation, GFAP expression, and auditory brainstem responses (ABRs) were analyzed at different time points.
- Auditory thresholds, latencies, interpeak latencies, and amplitudes were measured using ABRs.
Main Results:
- Microglia repopulated the MNTB to control levels by four weeks of age (18 days post-treatment cessation).
- Calcular innervation and GFAP expression recovered to control levels by four and seven weeks, respectively.
- Temporary microglial depletion elevated auditory thresholds and altered ABR parameters at four weeks, with significant recovery by seven weeks.
Conclusions:
- Microglia are vital for the proper formation and maturation of auditory neural circuits during early development.
- The study demonstrates that microglial functions in circuit refinement are retained even after the critical developmental period.
- These findings underscore the dynamic role of microglia in maintaining neural circuit integrity and function.
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