Multiple cannabinoid signaling cascades powerfully suppress recurrent excitation in the hippocampus
Multiple cannabinoid signaling cascades powerfully suppress recurrent excitation in the hippocampus
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DOI：
10.1073/pnas.2017590118
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发表时间：
2021-01-26
影响因子：
11.1
通讯作者：
Castillo, Pablo E.
中科院分区：
文献类型：
--
作者：
Jensen, Kyle R.;Berthoux, Coralie;Castillo, Pablo E.
循环兴奋性神经网络是不稳定的。在海马中，兴奋性苔藓细胞（MC）接受来自齿状颗粒细胞（GC）的强兴奋性输入，并投射回GC的近端树突。MCs通过沿海马背腹侧轴沿着靶向同侧和对侧齿状回（DG），形成广泛的复发性兴奋回路（GC-MC-GC），其失调可促进癫痫。我们最近报道，一个生理相关的模式MC活动诱导一个强大的形式的突触前长时程增强（LTP）的MC-GC传输，增强GC输出。如果不加以控制，这种LTP可能会干扰DG依赖的学习，比如依赖于稀疏GC放电的模式分离，甚至可能促进癫痫活动。有趣的是，MC轴突显示独特的高表达水平的1型大麻素受体（CB 1 R），但他们在MC-GC突触的作用知之甚少。使用啮齿动物海马切片，我们报告说，组成型活性CB 1 R可能通过β γ亚基选择性抑制MC对GC的输入，但不抑制MC对抑制性中间神经元的输入或CB 1 R敏感的对GC的抑制性输入。强CB 1 R活性也抑制LTP和GC输出。此外，GC短暂的内源性大麻素释放以两种不同的机制抑制MC-GC LTP：在通过β γ信号传导的诱导期间和在通过突触前后可塑性形式的α（i/o）信号传导的诱导之前。最后，一个单一的在体内暴露于外源性大麻素足以诱导这种突触前的metaplasticity。通过抑制兴奋性传递和可塑性，紧张性和阶段性CB 1 R活动在MC轴突终端可以保持稀疏的DG的性质，并防止失控的兴奋。
Recurrent excitatory neural networks are unstable. In the hippocampus, excitatory mossy cells (MCs) receive strong excitatory inputs from dentate granule cells (GCs) and project back onto the proximal dendrites of GCs. By targeting the ipsi- and contralateral dentate gyrus (DG) along the dorsoventral axis of the hippocampus, MCs form an extensive recurrent excitatory circuit (GC-MC-GC) whose dysregulation can promote epilepsy. We recently reported that a physiologically relevant pattern of MC activity induces a robust form of presynaptic long-term potentiation (LTP) of MC-GC transmission which enhances GC output. Left unchecked, this LTP may interfere with DG-dependent learning, like pattern separation-which relies on sparse GC firing-and may even facilitate epileptic activity. Intriguingly, MC axons display uniquely high expression levels of type-1 cannabinoid receptors (CB1Rs), but their role at MC-GC synapses is poorly understood. Using rodent hippocampal slices, we report that constitutively active CB1Rs, presumably via beta gamma subunits, selectively inhibited MC inputs onto GCs but not MC inputs onto inhibitory interneurons or CB1R-sensitive inhibitory inputs onto GCs. Tonic CB1R activity also inhibited LTP and GC output. Furthermore, brief endocannabinoid release from GCs dampened MC-GC LTP in two mechanistically distinct ways: during induction via beta gamma signaling and before induction via alpha(i/o) signaling in a form of presynaptic metaplasticity. Lastly, a single in vivo exposure to exogenous cannabinoids was sufficient to induce this presynaptic metaplasticity. By dampening excitatory transmission and plasticity, tonic and phasic CB1R activity at MC axon terminals may preserve the sparse nature of the DG and protect against runaway excitation.