Abstract
In the mammalian brain, auditory brainstem nuclei are arranged topographically according to acoustic frequency responsiveness. During postnatal development, the axon initial segment (AIS) of principal neurons undergoes structural refinement depending on location along the tonotopic axis within the medial nucleus of the trapezoid body (MNTB). However, the molecular mechanisms underlying the structural refinement of the AIS along the tonotopic axis in the auditory brainstem have not been explored. We tested the hypothesis that brain-derived neurotrophic factor (BDNF) is a molecular mediator of the structural development of the MNTB in an activity-dependent manner. Using BDNF heterozygous mutant (BDNF+/–) mice, we examined the impact of global BDNF reduction on structural and functional development of MNTB neurons by assessing AIS structure and associated intrinsic neuronal properties. BDNF reduction inhibits the structural and functional differentiation of principal neurons along the tonotopic axis in the MNTB. Augmented sound input during the critical period of development has been shown to enhance the structural refinement of the AIS of MNTB neurons. However, in BDNF +/– mice, MNTB neurons did not show this activity-dependent structural modification of the AIS following repeated sound stimulation. In addition, BDNF+/– mice lacked a defined isofrequency band of neuronal activity following exposure to 16 kHz sound, suggesting degradation of tonotopy. Taken together, structural development and functional refinement of auditory brainstem neurons require physiological levels of BDNF to establish proper tonotopic gradients.
Highlights
Along the auditory processing pathway, the topographic organization of neurons is important for determining where sound frequencies are processed within each auditory nucleus
To determine whether brain-derived neurotrophic factor (BDNF) mediates the structural refinement of the axon initial segment (AIS) along the tonotopic axis, we examined the effects of globally reduced BDNF on AIS
Using MAP2 and AnkG immunostaining, we examined the effect of reduced BDNF on AIS structural properties of medial nucleus of the trapezoid body (MNTB) neurons along the tonotopic axis in BDNF+/− mice (Figure 1C)
Summary
Along the auditory processing pathway, the topographic organization of neurons is important for determining where sound frequencies are processed within each auditory nucleus. In the MNTB, one of the key sound localization nuclei in the auditory brainstem, neurons are arranged with graded frequency-responsiveness (from high- to low-frequency) along the medio-lateral axis, respectively. BDNF Modulates the AIS of MNTB Neurons (e.g., soma size) are graded along the tonotopic axis in brainstem nuclei (Weatherstone et al, 2017; Akter et al, 2018). The length and location of the AIS, a key axonal domain responsible for action potential (AP) initiation and neuronal excitability, is dependent on cell location along the tonotopic axis in the chick and mouse (Kuba et al, 2006, 2014; Kim et al, 2019). The molecular mechanisms driving establishment of the tonotopic gradient of the AIS in the MNTB are unknown
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