Abstract:
During the first and second stages of postnatal development, neocortical neurons exhibit a wide range of spontaneous synchronous activity (SSA). Towards the end of the second postnatal week, the SSA is replaced by a more sparse and desynchronized firing pattern. The developmental desynchronization of neocortical spontaneous neuronal activity is thought to be intrinsically generated, since sensory deprivation from the periphery does not affect the time course of this transition. The extracellular protein reelin controls various aspects of neuronal development through multimodular signaling. However, so far it is unclear whether reelin contributes to the developmental desynchronization transition of neocortical neurons. The present study aims to investigate the role of reelin in postnatal cortical developmental desynchronization using a conditional reelin knockout (RelncKO) mouse model. Conditional reelin deficiency was induced during early postnatal development, and Ca2+ recordings were conducted from organotypic cultures (OTCs) of the somatosensory cortex. Our results show that both wild type (wt) and RelncKO exhibited an SSA pattern during the early postnatal week. However, at the end of the second postnatal week, wt OTCs underwent a transition to a desynchronized network activity pattern, while RelncKO activity remained synchronous. This changing activity pattern suggests that reelin is involved in regulating the developmental desynchronization of cortical neuronal network activity. Moreover, the developmental desynchronization impairment observed in RelncKO was rescued when RelncKO OTCs were co-cultured with wt OTCs. Finally, we show that the developmental transition to a desynchronized state at the end of the second postnatal week is not dependent on glutamatergic signaling. Instead, the transition is dependent on GABAAR and GABABR signaling. The results suggest that reelin controls developmental desynchronization through GABAAR and GABABR signaling.
摘要:
在出生后发育的第一和第二阶段,新皮层神经元表现出广泛的自发同步活动(SSA)。产后第二个星期快结束时,SSA被更稀疏和非同步的触发模式所取代。新皮层自发神经元活动的发育不同步被认为是内在产生的,因为来自外围的感觉剥夺不会影响这种转变的时间过程。细胞外蛋白reelin通过多模块信号传导控制神经元发育的各个方面。然而,到目前为止,尚不清楚reelin是否有助于新皮质神经元的发育去同步化转变。本研究旨在使用条件reelin基因敲除(RelncKO)小鼠模型研究reelin在出生后皮质发育不同步中的作用。在出生后早期发育过程中诱发了条件性reelin缺乏症,从体感皮层的器官型培养物(OTC)进行Ca2记录。我们的结果表明,野生型(wt)和RelncKO在出生后早期均表现出SSA模式。然而,在产后第二周结束时,WtOTC经历了向非同步网络活动模式的过渡,而RelncKO活动保持同步。这种变化的活动模式表明reelin参与调节皮质神经元网络活动的发育不同步。此外,当RelncKOOTC与wtOTC共培养时,在RelncKO中观察到的发育不同步障碍得以挽救。最后,我们表明,在出生后第二周结束时,发育过渡到去同步状态并不依赖于谷氨酸能信号。相反,转换依赖于GABAAR和GABABR信号传导。结果表明,reelin通过GABAAR和GABABR信号传导控制发育去同步。