Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla 92093, CA, United States; Academy of Biology and Biotechnology of Southern Federal University, 194/1 Stachki Ave, Rostov-na-Donu 344090, Russian Federation.
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla 92093, CA, United States.
Neurobiol Dis. 2018 Jul;115:1-8. doi: 10.1016/j.nbd.2018.03.005. Epub 2018 Mar 14.
Down syndrome (DS) is the most frequent genetic cause of developmental abnormalities leading to intellectual disability. One notable phenomenon affecting the formation of nascent neural circuits during late developmental periods is developmental switch of GABA action from depolarizing to hyperpolarizing mode. We examined properties of this switch in DS using primary cultures and acute hippocampal slices from Ts65Dn mice, a genetic model of DS. Cultures of DIV3-DIV13 Ts65Dn and control normosomic (2 N) neurons were loaded with FURA-2 AM, and GABA action was assessed using local applications. In 2 N cultures, the number of GABA-activated cells dropped from ~100% to 20% between postnatal days 3-13 (P3-P13) reflecting the switch in GABA action polarity. In Ts65Dn cultures, the timing of this switch was delayed by 2-3 days. Next, microelectrode recordings of multi-unit activity (MUA) were performed in CA3 slices during bath application of the GABA agonist isoguvacine. MUA frequency was increased in P8-P12 and reduced in P14-P22 slices reflecting the switch of GABA action from excitatory to inhibitory mode. The timing of this switch was delayed in Ts65Dn by approximately 2 days. Finally, frequency of giant depolarizing potentials (GDPs), a form of primordial neural activity, was significantly increased in slices from Ts65Dn pups at P12 and P14. These experimental evidences show that GABA action polarity switch is delayed in Ts65Dn model of DS, and that these changes lead to a delay in maturation of nascent neural circuits. These alterations may affect properties of neural circuits in adult animals and, therefore, represent a prospective target for pharmacotherapy of cognitive impairment in DS.
唐氏综合征（DS）是导致智力障碍的最常见的遗传原因之一。在晚期发育过程中，影响新生神经回路形成的一个显著现象是 GABA 作用从去极化向超极化模式的发育转换。我们使用 Ts65Dn 小鼠（DS 的遗传模型）的原代培养物和急性海马切片研究了这种转换的特性。在 DIV3-DIV13 的 Ts65Dn 和对照正常二倍体（2N）神经元培养物中加载 FURA-2 AM，并使用局部应用评估 GABA 作用。在 2N 培养物中，GABA 激活细胞的数量从出生后第 3-13 天（P3-P13）下降到 20%，反映了 GABA 作用极性的转换。在 Ts65Dn 培养物中，这种转换的时间延迟了 2-3 天。接下来，在浴应用 GABA 激动剂异古乌头碱期间，在 CA3 切片中进行多单位活动（MUA）的微电极记录。MUA 频率在 P8-P12 期间增加，在 P14-P22 期间减少，反映了 GABA 作用从兴奋模式向抑制模式的转换。这种转换的时间在 Ts65Dn 中延迟了大约 2 天。最后，在 P12 和 P14 的 Ts65Dn 幼鼠切片中，巨去极化电位（GDPs）的频率显著增加，GDPs 是原始神经活动的一种形式。这些实验证据表明，GABA 作用极性转换在 DS 的 Ts65Dn 模型中延迟，并且这些变化导致新生神经回路的成熟延迟。这些改变可能会影响成年动物神经回路的特性，因此代表了 DS 认知障碍药物治疗的潜在目标。
