Department of Biology, Brandeis University, Waltham, Massachusetts 02453.
Department of Biology, Brandeis University, Waltham, Massachusetts 02453
J Neurosci. 2021 Dec 1;41(48):9891-9905. doi: 10.1523/JNEUROSCI.1200-21.2021. Epub 2021 Oct 22.
Homeostatic plasticity maintains network stability by adjusting excitation, inhibition, or the intrinsic excitability of neurons, but the developmental regulation and coordination of these distinct forms of homeostatic plasticity remains poorly understood. A major contributor to this information gap is the lack of a uniform paradigm for chronically manipulating activity at different developmental stages. To overcome this limitation, we used designer receptors exclusively activated by designer drugs (DREADDs) to directly suppress neuronal activity in layer2/3 (L2/3) of mouse primary visual cortex of either sex at two important developmental timepoints: the classic visual system critical period [CP; postnatal day 24 (P24) to P29], and adulthood (P45 to P55). We show that 24 h of DREADD-mediated activity suppression simultaneously induces excitatory synaptic scaling up and intrinsic homeostatic plasticity in L2/3 pyramidal neurons during the CP, consistent with previous observations using prolonged visual deprivation. Importantly, manipulations known to block these forms of homeostatic plasticity when induced pharmacologically or via visual deprivation also prevented DREADD-induced homeostatic plasticity. We next used the same paradigm to suppress activity in adult animals. Surprisingly, while excitatory synaptic scaling persisted into adulthood, intrinsic homeostatic plasticity was completely absent. Finally, we found that homeostatic changes in quantal inhibitory input onto L2/3 pyramidal neurons were absent during the CP but were present in adults. Thus, the same population of neurons can express distinct sets of homeostatic plasticity mechanisms at different development stages. Our findings suggest that homeostatic forms of plasticity can be recruited in a modular manner according to the evolving needs of a developing neural circuit. Developing brain circuits are subject to dramatic changes in inputs that could destabilize activity if left uncompensated. This compensation is achieved through a set of homeostatic plasticity mechanisms that provide slow, negative feedback adjustments to excitability. Given that circuits are subject to very different destabilizing forces during distinct developmental stages, the forms of homeostatic plasticity present in the network must be tuned to these evolving needs. Here we developed a method to induce comparable homeostatic compensation during distinct developmental windows and found that neurons in the juvenile and mature brain engage strikingly different forms of homeostatic plasticity. Thus, homeostatic mechanisms can be recruited in a modular manner according to the developmental needs of the circuit.
内稳态可塑性通过调节神经元的兴奋、抑制或固有兴奋性来维持网络稳定性，但这些不同形式的内稳态可塑性的发育调节和协调仍知之甚少。造成这种信息差距的一个主要原因是缺乏一种在不同发育阶段长期控制活动的统一范式。为了克服这一限制，我们使用了 Designer Receptors Exclusively Activated by Designer Drugs（DREADDs），在两个重要的发育时间点，即经典视觉系统关键期[CP；出生后第 24 天（P24）至 P29]和成年期（P45 至 P55），直接抑制雄性和雌性小鼠初级视觉皮层第 2/3 层（L2/3）的神经元活动。我们表明，24 小时的 DREADD 介导的活动抑制，在 CP 期间同时诱导 L2/3 锥体神经元的兴奋性突触缩放和固有内稳态可塑性，这与使用长时间视觉剥夺的先前观察结果一致。重要的是，当通过药理学或视觉剥夺诱导时，已知会阻止这些形式的内稳态可塑性的操作也阻止了 DREADD 诱导的内稳态可塑性。我们接下来在成年动物中使用相同的范式来抑制活动。令人惊讶的是，虽然兴奋性突触缩放持续到成年期，但固有内稳态可塑性完全不存在。最后，我们发现，在 CP 期间，L2/3 锥体神经元上的抑制性量子输入的内稳态变化不存在，但在成年期存在。因此，在不同的发育阶段，同一神经元群体可以表达不同的内稳态可塑性机制。我们的研究结果表明，内稳态形式的可塑性可以根据发育中神经回路的不断发展的需求以模块化的方式被招募。发育中的大脑回路会受到输入的剧烈变化的影响，如果不进行补偿，这些变化可能会使活动不稳定。这种补偿是通过一系列内稳态可塑性机制实现的，这些机制对内兴奋性提供缓慢的负反馈调节。鉴于在不同的发育阶段，回路会受到非常不同的去稳定力的影响，因此，网络中存在的内稳态可塑性形式必须针对这些不断发展的需求进行调整。在这里，我们开发了一种在不同发育窗口诱导类似内稳态补偿的方法，并发现幼年期和成熟期大脑中的神经元采用了截然不同的内稳态可塑性形式。因此，内稳态机制可以根据回路的发育需求以模块化的方式被招募。
