GABAB 和 GABAA 受体介导的发育过程中上下状态的调节,The Journal of Physiology

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GABAB 和 GABAA 受体介导的发育过程中上下状态的调节
The Journal of Physiology ( IF 4.7 ) Pub Date : 2022-04-01 , DOI: 10.1113/jp282736
Ani Kaplanian _{1,

2} , Michael Vinos _{1,

3} , Irini Skaliora _{1,

3}

Affiliation

慢速振荡是非快速眼动睡眠的标志，以及它们的细胞对应物，上下状态 (UDS)，被认为是反映内在网络组织的皮层动力学特征。尽管先前的研究已经探索了抑制在调节 UDS 中的作用，但对于这种作用是否会随着成熟而改变知之甚少。这是令人惊讶的，因为慢振荡和 UDS 都表现出显着的年龄依赖性变化。为了阐明 GABA _B和 GABA _{A受体对 UDS 活性的发育影响，我们在}体外同时进行了局部场电位和细胞内记录，在年轻和成年雄性小鼠的脑切片中，分别使用选择性阻滞剂 CGP55845 和非饱和浓度的 gabazine。GABA _B和 GABA _A信号传导的阻断显示出年龄分化的功能。CGP55845 导致年轻动物的 Down 状态持续时间增加，但成年动物减少。Gabazine 诱发了两个年龄段的尖峰和波放电；然而，当年轻的网络完全癫痫时，成年人仍然保持产生 UDS 的能力。此外，微型抑制性突触后电流的电压钳记录显示，gabazine 选择性地阻断相位电流，特别是涉及突触后机制。_{后者表现出明显的成熟变化，表明 GABA A}的亚基组成不同年轻与. 成年动物。事实上，随后在地西泮（纳摩尔或微摩尔浓度）下的局部场电位记录表明，与成人相比，由含 α1 亚基的 GABA _A受体介导的药物经典结合位点的机制对年轻网络的 Up 状态启动做出了更大的贡献. 总之，这些发现有助于阐明皮质网络活动成熟的机制，并增强我们对神经发育障碍出现的理解。

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GABAB- and GABAA-receptor-mediated regulation of Up and Down states across development

Slow oscillations, the hallmark of non-REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered a signature of cortical dynamics that reflect the intrinsic network organization. Although previous studies have explored the role of inhibition in regulating UDSs, little is known about whether this role changes with maturation. This is surprising since both slow oscillations and UDSs exhibit significant age-dependent alterations. To elucidate the developmental impact of GABA_B and GABA_A receptors on UDS activity, we conducted simultaneous local field potentials and intracellular recordings ex vivo, in brain slices of young and adult male mice, using selective blockers, CGP55845 and a non-saturating concentration of gabazine, respectively. Blockade of both GABA_B and GABA_A signalling showed age-differentiated functions. CGP55845 caused an increase in Down state duration in young animals, but a decrease in adults. Gabazine evoked spike and wave discharges in both ages; however, while young networks became completely epileptic, adults maintained the ability to generate UDSs. Furthermore, voltage clamp recordings of miniature inhibitory postsynaptic currents revealed that gabazine selectively blocks phasic currents, particularly involving postsynaptic mechanisms. The latter exhibit clear maturational changes, suggesting a different subunit composition of GABA_A receptors in young vs. adult animals. Indeed, subsequent local field potential recordings under diazepam (nanomolar or micromolar concentrations) revealed that mechanisms engaging the drug's classical binding site, mediated by α1-subunit-containing GABA_A receptors, make a bigger contribution to Up state initiation in young networks compared to adults. Taken together, these findings help clarify the mechanisms that underlie the maturation of cortical network activity and enhance our understanding regarding the emergence of neurodevelopmental disorders.

更新日期：2022-04-01

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