Cannabinoid CB1 Receptor in Dorsal Telencephalic Glutamatergic Neurons: Distinctive Sufficiency for Hippocampus-Dependent and Amygdala-Dependent Synaptic and Behavioral Functions
Cannabinoid CB1 Receptor in Dorsal Telencephalic Glutamatergic Neurons: Distinctive Sufficiency for Hippocampus-Dependent and Amygdala-Dependent Synaptic and Behavioral Functions
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DOI：
10.1523/jneurosci.4171-12.2013
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发表时间：
2013-06-19
影响因子：
5.3
通讯作者：
Lutz, Beat
中科院分区：
文献类型：
--
作者：
Ruehle, Sabine;Remmers, Floor;Lutz, Beat
当前神经科学的一个主要目标是了解蛋白质功能，神经活动和行为之间的因果关系。大麻素CB1受体在不同的神经元亚群中表达，并参与微调兴奋性和抑制性神经传递。使用条件性基因敲除小鼠的研究揭示了背侧端脑谷氨酸能神经元中表达的CB 1受体在突触可塑性和行为中的必要作用，但这种表达是否也足以维持大脑功能仍有待确定。我们应用遗传策略重建完整的野生型CB1受体功能完全在背侧端脑神经元和内源性大麻素依赖性突触过程和行为进行了研究。使用这种方法，我们部分恢复了焦虑样行为中全局CB1受体缺失的表型，并完全恢复了化学诱导癫痫样发作的海马依赖性神经保护作用。这些特征与海马去极化诱导的兴奋抑制（DSE）相吻合，DSE是海马能神经元突触可塑性的CB1受体依赖性形式。相比之下，CB1受体的背侧端脑海马能神经元的救援延长了DSE在杏仁核的时间过程中，和受损的恐惧消退听觉恐惧条件反射。这些数据表明，CB1受体在背侧端脑cabinamatergic神经元起着足够的作用，以控制神经元的功能，在很大程度上是依赖于海马体，而它是不够的适当的杏仁核功能，提示杏仁核中的内源性大麻素信号的一个意想不到的复杂的电路调节。我们的数据铺平了道路，以更好地了解神经网络的行为背景下，通过微调干扰突触传递过程。
A major goal in current neuroscience is to understand the causal links connecting protein functions, neural activity, and behavior. The cannabinoid CB1 receptor is expressed in different neuronal subpopulations, and is engaged in fine-tuning excitatory and inhibitory neurotransmission. Studies using conditional knock-out mice revealed necessary roles of CB1 receptor expressed in dorsal telencephalic glutamatergic neurons in synaptic plasticity and behavior, but whether this expression is also sufficient for brain functions is still to be determined. We applied a genetic strategy to reconstitute full wild-type CB1 receptor functions exclusively in dorsal telencephalic glutamatergic neurons and investigated endocannabinoid-dependent synaptic processes and behavior. Using this approach, we partly restored the phenotype of global CB1 receptor deletion in anxiety-like behaviors and fully restored hippocampus-dependent neuroprotection from chemically induced epileptiform seizures. These features coincided with a rescued hippocampal depolarization-induced suppression of excitation (DSE), a CB1 receptor-dependent form of synaptic plasticity at glutamatergic neurons. By comparison, the rescue of the CB1 receptor on dorsal telencephalic glutamatergic neurons prolonged the time course of DSE in the amygdala, and impaired fear extinction in auditory fear conditioning. These data reveal that CB1 receptor in dorsal telencephalic glutamatergic neurons plays a sufficient role to control neuronal functions that are in large part hippocampus-dependent, while it is insufficient for proper amygdala functions, suggesting an unexpectedly complex circuit regulation by endocannabinoid signaling in the amygdala. Our data pave the way to a better understanding of neuronal networks in the context of behavior, by fine-tuned interference with synaptic transmission processes.