Activity-dependent history in hippocampal neurons dictates temporal dynamics of homeostatic synaptic scaling

Neural circuits utilize a host of homeostatic plasticity mechanisms, including synaptic scaling, to maintain stability in circuits undergoing experience-dependent remodeling necessary for information processing. During synaptic scaling, compensatory adaptations in synaptic strength are induced after chronic manipulations in neuronal firing, but our understanding of this process is largely limited to its initial induction. How these homeostatic synaptic adaptations evolve when activity renormalizes and their impact on subsequent homeostatic compensation are both poorly understood. To examine these issues, we investigated whether a previous history of homeostatic scaling in networks of cultured hippocampal neurons altered their subsequent homeostatic responses to chronic activity manipulations. Unexpectedly, we found that a history of synaptic scaling strongly suppressed future scaling to the same, and even opposite, activity challenges. This history-dependent suppression was specific for future homeostatic compensation, as networks with a prior scaling history showed no deficits in the chemical induction of long-term potentiation (cLTP), a Hebbian form of synaptic plasticity. Hippocampal neurons with a prior scaling history exhibited normal engagement of activity-dependent signaling during subsequent activity challenges (as assessed by examination of the ERK/MAPK pathway) but demonstrated widespread alterations in activity-dependent transcriptional神经环路借助包括突触缩放（synaptic scaling）在内的多种稳态可塑性（homeostatic plasticity）机制，以在信息处理所必需的经验依赖性重塑过程中维持环路稳定性。在突触缩放过程中，神经元放电活动经长期调控后会诱发突触强度的代偿性适应，但目前我们对该过程的认知大多局限于其初始诱导阶段。当活动恢复正常时，这些稳态突触适应性变化会如何演变，以及它们对后续稳态代偿的影响，目前均尚不明确。为探究上述问题，本研究针对体外培养的海马神经元网络中既往存在的稳态缩放史是否会改变其后续对长期活动调控的稳态应答展开了调查。出乎意料的是，我们发现既往存在突触缩放史的网络，其对相同乃至相反活动刺激的后续突触缩放反应会受到显著抑制。这种依赖于既往史的抑制效应仅针对后续稳态代偿：具有既往缩放史的网络，其化学诱导长时程增强（cLTP，long-term potentiation）——一种赫布型突触可塑性（Hebbian synaptic plasticity）——的过程并未出现缺陷。具有既往缩放史的海马神经元，在后续活动刺激下（通过ERK/MAPK通路检测评估）的活动依赖性信号激活表现正常，但在活动依赖性转录过程中呈现出广泛的异常改变。