Huang Jui-Yen, Lynn Miskus Marisha, Lu Hui-Chen
Department of Psychological and Brain Sciences, the Linda and Jack Gill Center for Bimolecular Sciences, Indiana University, Bloomington, Indiana 47405, and.
The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030.
J Neurosci. 2017 Dec 13;37(50):12094-12105. doi: 10.1523/JNEUROSCI.1174-17.2017. Epub 2017 Nov 2.
Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known for their potent effects on cell proliferation/differentiation and cortical patterning in the developing brain. However, little is known regarding the roles of FGFs/FGFRs in cortical circuit formation. Here we show that //3 and /// mRNAs are expressed in the developing primary somatosensory (S1) barrel cortex. Barrel cortex layer IV spiny stellate cells (bSCs) are the primary recipients of ascending sensory information via thalamocortical axons (TCAs). Detail quantification revealed distinctive phases for bSC dendritogenesis: orienting dendrites toward TCAs, adding dendritic segments, and elongating dendritic length, while maintaining dendritic patterns. Deleting // in bSCs had minimal impact on dendritic polarity but transiently increased the number of dendritic segments. However, 6 d later, FGFR1/2/3 loss of function reduced dendritic branch numbers. These data suggest that FGFs/FGFRs have a role in stabilizing dendritic patterning. Depolarization of cultured mouse cortical neurons upregulated the levels of several / mRNAs within 2 h. , within 6 h of systemic kainic acid administration at postnatal day 6, mRNA levels of , , , and in S1 cortices were enhanced, and this was accompanied by exuberant dendritogenesis of bSCs by 24 h. Deleting // abolished kainic acid-induced bSC dendritic overgrowth. Finally, FGF9/10 gain of function also resulted in extensive dendritogenesis. Together, our data suggest that FGFs/FGFRs can be regulated by glutamate transmission to modulate/stabilize bSC dendritic complexity. Both male and female mice were used for our study. Glutamatergic transmission plays critical roles in cortical circuit formation. Its dysregulation has been proposed as a core factor in the etiology of many neurological diseases. We found that excessive glutamate transmission upregulated mRNA expression of and their ligands Deleting // not only impaired bSC dendritogenesis but also abolished glutamate transmission-induced dendritic overgrowth. Overexpressing FGF9 or FGF10 in cortical glutamatergic neurons results in excessive dendritic outgrowth within 24 h, resembling the changes induced by excessive glutamate transmission. Our findings provide strong evidence for the physiological role of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) in establishing and maintaining cortical circuits. Perturbing the expression levels of FGFs/FGFRs by excessive glutamatergic neurotransmission could lead to abnormal neuronal circuits, which may contribute to neurological and psychiatric disease.
成纤维细胞生长因子（FGFs）和成纤维细胞生长因子受体（FGFRs）因其对发育中大脑的细胞增殖/分化及皮质模式形成具有强大作用而闻名。然而，关于FGFs/FGFRs在皮质回路形成中的作用却知之甚少。在此我们表明，β和γ mRNAs在发育中的初级体感（S1）桶状皮质中表达。桶状皮质IV层棘状星状细胞（bSCs）是通过丘脑皮质轴突（TCAs）接收上行感觉信息的主要细胞。详细定量分析揭示了bSC树突发生的不同阶段：将树突朝向TCAs定向、增加树突节段以及延长树突长度，同时维持树突模式。在bSCs中删除β对树突极性影响极小，但会短暂增加树突节段数量。然而，6天后，FGFR1/2/3功能丧失会减少树突分支数量。这些数据表明FGFs/FGFRs在稳定树突模式中发挥作用。培养的小鼠皮质神经元去极化在2小时内上调了几种γ mRNAs的水平。在出生后第6天全身给予 kainic 酸6小时内，S1皮质中β、γ、δ和ε的mRNA水平升高，并且在24小时时伴有bSCs旺盛的树突发生。删除β可消除kainic酸诱导的bSC树突过度生长。最后，FGF9/10功能获得也导致广泛的树突发生。总之，我们的数据表明FGFs/FGFRs可受谷氨酸传递调节，以调节/稳定bSC树突复杂性。我们的研究使用了雄性和雌性小鼠。谷氨酸能传递在皮质回路形成中起关键作用。其失调被认为是许多神经疾病病因的核心因素。我们发现过量的谷氨酸传递上调了β和γ及其配体的mRNA表达。删除β不仅损害bSC树突发生，还消除了谷氨酸传递诱导的树突过度生长。在皮质谷氨酸能神经元中过表达FGF9或FGF10会在24小时内导致过度的树突生长，类似于过量谷氨酸传递诱导的变化。我们的研究结果为成纤维细胞生长因子（FGFs）和成纤维细胞生长因子受体（FGFRs）在建立和维持皮质回路中的生理作用提供了有力证据。通过过量的谷氨酸能神经传递干扰FGFs/FGFRs的表达水平可能导致异常的神经元回路，这可能导致神经和精神疾病。
