Pascual Cuadrado Diego, Wierczeiko Anna, Hewel Charlotte, Gerber Susanne, Lutz Beat
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Front Synaptic Neurosci. 2021 Apr 8;13:660718. doi: 10.3389/fnsyn.2021.660718. eCollection 2021.
Brain homeostasis is the dynamic equilibrium whereby physiological parameters are kept actively within a specific range. The homeostatic range is not fixed and may change throughout the individual's lifespan, or may be transiently modified in the presence of severe perturbations. The endocannabinoid system has emerged as a safeguard of homeostasis, e.g., it modulates neurotransmission and protects neurons from prolonged or excessively strong activation. We used genetically engineered mouse lines that lack the cannabinoid type-1 receptor (CB1) either in dorsal telencephalic glutamatergic or in forebrain GABAergic neurons to create new allostatic states, resulting from alterations in the excitatory/inhibitory (E/I) balance. Previous studies with these two mouse lines have shown dichotomic results in the context of behavior, neuronal morphology, and electrophysiology. Thus, we aimed at analyzing the transcriptomic profile of the hippocampal CA region from these mice in the basal condition and after a mild behavioral stimulation (open field). Our results provide insights into the gene networks that compensate chronic E/I imbalances. Among these, there are differentially expressed genes involved in neuronal and synaptic functions, synaptic plasticity, and the regulation of behavior. Interestingly, some of these genes, e.g., , and , and related pathways showed a dichotomic expression, i.e., they are up-regulated in one mutant line and down-regulated in the other one. Subsequent interrogation on the source of the alterations at transcript level were applied using exon-intron split analysis. However, no strong directions toward transcriptional or post-transcriptional regulation comparing both mouse lines were observed. Altogether, the dichotomic gene expression observed and their involved signaling pathways are of interest because they may act as "switches" to modulate the directionality of neural homeostasis, which then is relevant for pathologies, such as stress-related disorders and epilepsy.
脑内稳态是一种动态平衡，通过这种平衡，生理参数被积极地维持在特定范围内。稳态范围并非固定不变，可能在个体的整个生命周期中发生变化，或者在存在严重干扰的情况下被短暂改变。内源性大麻素系统已成为一种稳态保障机制，例如，它调节神经传递并保护神经元免受长时间或过度强烈的激活。我们使用了基因工程小鼠品系，这些品系在背侧端脑谷氨酸能神经元或前脑γ-氨基丁酸能神经元中缺乏1型大麻素受体（CB1），以产生由于兴奋/抑制（E/I）平衡改变而导致的新的异稳态。先前对这两种小鼠品系的研究在行为、神经元形态和电生理学方面显示出二分法的结果。因此，我们旨在分析这些小鼠在基础状态和轻度行为刺激（旷场试验）后海马CA区的转录组谱。我们的结果为补偿慢性E/I失衡的基因网络提供了见解。其中，有参与神经元和突触功能、突触可塑性以及行为调节的差异表达基因。有趣的是，这些基因中的一些，例如 ，以及 ，和相关途径表现出二分法表达，即它们在一个突变品系中上调而在另一个突变品系中下调。随后使用外显子-内含子分裂分析对转录水平改变的来源进行了探究。然而，在比较这两种小鼠品系时，未观察到朝向转录或转录后调节的强烈趋势。总之，观察到的二分法基因表达及其涉及的信号通路令人感兴趣，因为它们可能充当“开关”来调节神经稳态的方向性，这进而与诸如应激相关障碍和癫痫等病理状态相关。
