McLellan Kristine, Sabbagh Sima, Takahashi Momoko, Hong Hui, Wang Yuan, Sanchez Jason Tait
Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60208, USA.
Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
Biology (Basel). 2024 Oct 29;13(11):877. doi: 10.3390/biology13110877.
Neurotrophins are proteins that mediate neuronal development using spatiotemporal signaling gradients. The chicken nucleus magnocellularis (NM), an analogous structure to the mammalian anteroventral cochlear nucleus, provides a model system in which signaling between the brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) is temporally regulated. In the NM, TrkB expression is high early in development (embryonic [E] day 9) and is downregulated until maturity (E18-21). It is currently unknown how BDNF-TrkB signaling affects neuronal properties throughout development and across a spatial (i.e., frequency) axis. To investigate this, we exogenously applied BDNF onto NM neurons ex vivo and studied intrinsic properties using whole-cell patch clamp electrophysiology. Early in development (E13), when TrkB expression is detectable with immunohistochemistry, BDNF application slowed the firing of high-frequency NM neurons, resembling an immature phenotype. Current measurements and biophysical modeling revealed that this was mediated by a decreased conductance of the voltage-dependent potassium channels. Interestingly, this effect was seen only in high-frequency neurons and not in low-frequency neurons. BDNF-TrkB signaling induced minimal changes in late-developing NM neurons (E20-21) of high and low frequencies. Our results indicate that normal developmental downregulation of BDNF-TrkB signaling promotes neuronal maturation tonotopically in the auditory brainstem, encouraging the appropriate development of neuronal properties.
神经营养因子是一类通过时空信号梯度介导神经元发育的蛋白质。鸡的巨细胞核（NM）是哺乳动物前腹侧耳蜗核的类似结构，它提供了一个模型系统，在其中脑源性神经营养因子（BDNF）和酪氨酸受体激酶B（TrkB）之间的信号传导受到时间调控。在NM中，TrkB的表达在发育早期（胚胎期[E]第9天）很高，然后下调直至成熟（E18 - 21）。目前尚不清楚BDNF - TrkB信号在整个发育过程中以及跨空间（即频率）轴如何影响神经元特性。为了研究这一点，我们在体外将BDNF外源性应用于NM神经元，并使用全细胞膜片钳电生理学研究其内在特性。在发育早期（E13），当通过免疫组织化学可检测到TrkB表达时，应用BDNF会减慢高频NM神经元的放电，类似于未成熟的表型。电流测量和生物物理建模表明，这是由电压依赖性钾通道的电导降低介导的。有趣的是，这种效应仅在高频神经元中出现，而在低频神经元中未出现。BDNF - TrkB信号在发育后期的高频和低频NM神经元（E20 - 21）中引起的变化最小。我们的结果表明，BDNF - TrkB信号的正常发育性下调促进了听觉脑干中神经元的音调拓扑成熟，促进了神经元特性的适当发育。
