Behavioural Neuroscience Laboratory, Department of Psychiatry, Monash University, Clayton, Victoria 3168, Australia.
Psychoneuroendocrinology Laboratory, Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia.
Mol Cell Neurosci. 2018 Apr;88:177-188. doi: 10.1016/j.mcn.2018.02.001. Epub 2018 Feb 3.
Brain-derived neurotrophic factor (BDNF) is known to play a critical role early in the development of cortical GABAergic interneurons. Recently our laboratory and others have shown protracted development of specific subpopulations of GABAergic interneurons extending into adolescence. BDNF expression also changes significantly across adolescent development. However the role of BDNF in regulating GABAergic changes across adolescence remains unclear. Here, we performed a week-by-week analysis of the protein expression and cell density of three major GABAergic interneurons, parvalbumin (PV), somatostatin (SST) and calretinin (Cal) in the medial prefrontal cortex from prepubescence (week 3) to adulthood (week 12). In order to assess how BDNF and sex might influence the adolescent trajectory of GABAergic interneurons we compared WT as well as BDNF heterozygous (+/-) male and female mice. In both males and females PV expression increases during adolescent development in the mPFC. Compared to wild-types, PV expression was reduced in male but not female BDNF+/- mice throughout adolescent development. This reduction in protein expression corresponded with reduced cell density, specifically within the infralimbic prefrontal cortex. SST expression increased in early adolescent WT females and this upregulation was delayed in BDNF+/-. SST cell density also increased in early adolescent mPFC of WT female mice, with BDNF+/- again showing a reduced pattern of expression. Cal protein expression was also sex-dependently altered across adolescence with WT males showing a steady decline but that of BDNF+/- remaining unaltered. Reduced cell density in on the other hand was observed particularly in male BDNF+/- mice. In females, Cal protein expression and cell density remained largely stable. Our results show that PV, SST and calretinin interneurons are indeed still developing into early adolescence in the mPFC and that BDNF plays a critical, sex-specific role in mediating expression and cell density.
脑源性神经营养因子 (BDNF) 已知在皮质 GABA 能中间神经元的早期发育中发挥关键作用。最近，我们实验室和其他实验室已经表明，特定 GABA 能中间神经元亚群的发育持续到青春期。BDNF 的表达也在青春期发育过程中发生显著变化。然而，BDNF 在调节整个青春期 GABA 能变化中的作用尚不清楚。在这里，我们对青春期前（第 3 周）到成年期（第 12 周）内侧前额叶皮质中三种主要 GABA 能中间神经元（PV、SST 和 Cal）的蛋白质表达和细胞密度进行了每周一次的分析。为了评估 BDNF 和性别如何影响 GABA 能中间神经元的青少年轨迹，我们比较了 WT 以及 BDNF 杂合子（+/ -）雄性和雌性小鼠。在雄性和雌性小鼠中，PV 的表达在青春期发育过程中增加。与野生型相比，在整个青春期发育过程中，BDNF+/ - 雄性小鼠的 PV 表达减少，但雌性小鼠的 PV 表达没有减少。这种蛋白表达的减少与细胞密度的减少相对应，特别是在边缘下前额皮质内。SST 的表达在青春期早期 WT 雌性中增加，而 BDNF+/ - 的这种上调被延迟。WT 雌性小鼠的早期青春期 mPFC 中 SST 细胞密度也增加，BDNF+/- 再次表现出减少的表达模式。Cal 蛋白表达也在青春期经历性别依赖性改变，WT 雄性表现出稳定下降，但 BDNF+/- 保持不变。另一方面，细胞密度的减少在雄性 BDNF+/- 小鼠中尤为明显。在雌性中，Cal 蛋白表达和细胞密度基本保持稳定。我们的研究结果表明，PV、SST 和 calretinin 中间神经元确实仍在 mPFC 中发育到青春期早期，BDNF 在介导表达和细胞密度方面发挥着关键的、性别特异性的作用。
