Brain-Derived Neurotrophic Factor Is Involved in Activity-Dependent Tonotopic Refinement of MNTB Neurons

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.

Impacts of Perinatal Nicotine Exposure on nAChR Expression and Glutamatergic Synaptic Transmission in the Mouse Auditory Brainstem

“…On the other hand, artificially augmenting nAChR signaling to enhance medial olivocochlear efferent activity impairs glutamatergic neurotransmission at the calyx-MNTB synapse and eliminates tonotopic patterning of intrinsic properties of MNTB neurons 71 . Interestingly, our previous work has observed elimination of MNTB tonotopic gradients in mice with global BDNF reduction 72 , and neonatal exposure to nicotine reduces brain BDNF levels 73 . Therefore, it is possible that reduction of BDNF following chronic nicotine exposure is contributing to the PNE-induced synaptic impairments.…”

Tonotopic differentiation of presynaptic neurotransmitter‐releasing machinery in the auditory brainstem during the prehearing period and its selective deficits in Fmr1 knockout mice

“…FMRP is identified as a potential mechanism underlying the organized maturation of essential presynaptic proteins. Together with other known regulators of tonotopy (neurotrophic factors: Wollet & Kim, 2022; ephrin signals: Hoshino et al., 2021; Huffman & Cramer, 2007; hox genes: Karmakar et al., 2017; protein‐coding gene Neurod 1: Macova et al., 2019; natriuretic peptide receptor Npr2: Lu et al., 2014; glial‐neuron interaction signal: Milinkeviciute et al., 2021), this finding opens a new direction for understanding auditory tonotopic development and the emergence of tonotopic alterations in animal models of FXS (Kim et al., 2013; Strumbos et al., 2010) and autism (Anomal et al., 2015; Engineer et al., 2014).…”