Johnson-Venkatesh Erin M, Umemori Hisashi
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Neurosci. 2025 Sep 2. doi: 10.1523/JNEUROSCI.1182-24.2025.
The proper development of excitatory/inhibitory balance is critical for brain function, as any imbalance has been associated with myriad neuropsychiatric disorders. How this balance evolves during synaptic development remains unclear. To address this question, we examine how manipulations of SIRPα, a cell-adhesion molecule that organizes excitatory synaptic development in the hippocampus, affect inhibitory synaptogenesis to maintain excitatory/inhibitory balance, using mice of either sex. SIRPα primarily localizes to excitatory synapses. Overexpression or inactivation of SIRPα in a single neuron in hippocampal cultures affects excitatory, but not inhibitory synapses formed onto the SIRPα-manipulated neuron, indicating that SIRPα is an excitatory, but not inhibitory, synapse organizer. Despite this, bath application of SIRPα's ectodomain increases inhibitory synapses in culture, and global inactivation of SIRPα and during critical periods functionally decreases both excitatory and inhibitory synapses in the hippocampus. By using various conditional KO mice, we found that SIRPα from pyramidal neurons, but not from inhibitory interneurons, astrocytes, or microglia is necessary for proper inhibitory synapse development. Interestingly, inactivation of SIRPα from most pyramidal neurons is necessary to impact inhibitory synaptic development, suggesting that inhibitory synaptogenesis in the hippocampus is driven by the strength of excitation in the pyramidal-neuron network, and not by a change in excitatory input to a single cell. Consistently, the effect of SIRPα's ectodomain on inhibitory, but not excitatory synaptogenesis is blocked by global neural activity inhibition. We propose that the development of inhibitory synapses in the hippocampus is regulated by network-level excitatory activity to evolve excitatory/inhibitory balance. How excitatory/inhibitory (E/I) balance evolves during development is still unknown. We manipulated an excitatory synapse organizing cell-adhesion molecule, SIRPα, in the hippocampus and examined how inhibitory synaptogenesis is affected to maintain E/I balance. Global inactivation of SIRPα during a critical period functionally decreases both excitatory and inhibitory synapses. Using many mouse mutants and manipulations, we identified that inactivation of SIRPα from most pyramidal neurons is necessary to impact inhibitory synaptogenesis and that the effect of SIRPα on inhibitory synaptogenesis is blocked by global neural activity inhibition. Therefore, we propose that inhibitory synaptogenesis is regulated by the excitatory drive at the network level and not at the single-cell level. Our work reveals a fundamental mechanism that develops E/I balance.
兴奋性/抑制性平衡的正常发育对脑功能至关重要，因为任何失衡都与多种神经精神疾病相关。这种平衡在突触发育过程中如何演变仍不清楚。为了解决这个问题，我们使用雌雄小鼠研究了信号调节蛋白α（SIRPα）的调控对抑制性突触形成的影响，SIRPα是一种在海马体中组织兴奋性突触发育的细胞粘附分子，以此来维持兴奋性/抑制性平衡。SIRPα主要定位于兴奋性突触。在海马体培养物中的单个神经元中过表达或失活SIRPα会影响在该SIRPα被操控的神经元上形成的兴奋性突触，但不影响抑制性突触，这表明SIRPα是兴奋性而非抑制性突触组织者。尽管如此，在培养物中浴加SIRPα的胞外域会增加抑制性突触，而在关键期整体失活SIRPα在功能上会减少海马体中的兴奋性和抑制性突触。通过使用各种条件性敲除小鼠，我们发现锥体神经元而非抑制性中间神经元、星形胶质细胞或小胶质细胞中的SIRPα对于正常的抑制性突触发育是必需的。有趣的是，大多数锥体神经元中SIRPα的失活对于影响抑制性突触发育是必要的，这表明海马体中的抑制性突触形成是由锥体神经元网络中的兴奋强度驱动的，而不是由单个细胞兴奋性输入的变化驱动的。一致地，SIRPα胞外域对抑制性而非兴奋性突触形成的影响被整体神经活动抑制所阻断。我们提出海马体中抑制性突触的发育受网络水平的兴奋性活动调控，以形成兴奋性/抑制性平衡。兴奋性/抑制性（E/I）平衡在发育过程中如何演变仍然未知。我们在海马体中操控一种兴奋性突触组织细胞粘附分子SIRPα，并研究抑制性突触形成如何受到影响以维持E/I平衡。在关键期整体失活SIRPα在功能上会减少兴奋性和抑制性突触。通过使用多种小鼠突变体和操控手段，我们确定大多数锥体神经元中SIRPα的失活对于影响抑制性突触形成是必要的，并且SIRPα对抑制性突触形成的影响被整体神经活动抑制所阻断。因此，我们提出抑制性突触形成受网络水平而非单细胞水平的兴奋性驱动调控。我们的工作揭示了一种形成E/I平衡的基本机制。
