Ca²⁺/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like brain-derived neurotrophic factor (BDNF). Here, we show that neuromodulator secretion is indeed reduced in mouse α- and βCaMKII-deficient (αβCaMKII double-knockout [DKO]) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αβCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wild-type neurons produced a similar reduction. Reduced neuromodulator expression in αβCaMKII DKO neurons was restored by active βCaMKII but not inactive βCaMKII or αCaMKII, and by CaMKII downstream effectors that promote cAMP-response element binding protein (CREB) phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to βCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.

钙²⁺/钙调蛋白依赖性激酶II（CaMKII）以多种方式调节突触可塑性，据推测包括分泌神经调节剂，如脑源性神经营养因子（BDNF）。在这里，我们显示了在小鼠α-和βCaMKII缺陷型（αβCaMKII双敲除[DKO]）海马神经元中神经调节剂的分泌确实减少了。但是，这不是由于分泌效率降低或神经调节剂囊泡运输降低，而是由于突触时神经调节剂水平降低了40％，新神经调节剂囊泡向轴突的传递降低了50％。αβCaMKII耗竭大大降低了神经调节因子的表达。在野生型神经元中阻断BDNF分泌或清除BDNF也会产生类似的减少。ββCaMKIIDKO神经元中神经调节剂表达的降低可通过活性βCaMKII来恢复，但不能通过无活性βCaMKII或αCaMKII来恢复，以及通过CaMKII下游效应子促进cAMP反应元件结合蛋白（CREB）磷酸化。这些数据表明，CaMKII在反馈回路中调节神经调节，该反馈回路将神经调节剂的分泌与βCaMKII和CREB依赖的神经调节剂的表达以及轴突靶向结合，但是CaMKII对于分泌过程本身是必不可少的。