Ade Kristen K, Lovinger David M
Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC 20007, USA.
J Neurosci. 2007 Feb 28;27(9):2403-9. doi: 10.1523/JNEUROSCI.2916-06.2007.
Long-term changes in synaptic efficacy produced by high-frequency stimulation (HFS) of glutamatergic afferents to the rat dorsolateral striatum exhibit heterogeneity during early stages of postnatal development. Whereas HFS most often induces striatal long-term potentiation (LTP) in rats postnatal day 12 (P12)-P14, the same stimulation tends to induce long-term depression (LTD) at ages P16-P34. Previous studies have shown that striatal LTD induction depends on retrograde endocannabinoid signaling and activation of the CB1 cannabinoid receptor. It is also known that levels of one of the primary endogenous CB1 receptor agonists, anandamide (AEA), increases during development in whole-brain samples. In the present study, we sought to determine whether this developmental increase in AEA also takes place in striatal tissue and whether increased AEA levels contribute to the postnatal switch in the response to HFS. We observed a pronounced increase in striatal levels of AEA, but not the other major endogenous cannabinoid 2-arachidonoylglycerol (2-AG), during the postnatal period characterized by the switch from LTP to LTD. Furthermore, application of synthetic AEA during HFS in field recordings of slices from P12-P14 rats allowed for induction of LTD whereas blocking the CB1 receptor during HFS in animals P16-P34 resulted in expression of LTP. However, blocking 2-AG synthesis with the DAG-lipase inhibitor tetrahydrolipstatin did not alter HFS-induced striatal LTD. In addition, synaptic depression produced by a synthetic CB1 agonist was similar across development. Together, these findings suggest that the robust developmental increase in striatal AEA may be the key factor in the emergence of HFS-induced striatal LTD.
对大鼠背外侧纹状体谷氨酸能传入神经进行高频刺激（HFS）所产生的突触效能长期变化在出生后发育的早期阶段表现出异质性。在出生后第12天（P12）-P14的大鼠中，HFS最常诱导纹状体长期增强（LTP），而在P16-P34年龄段，相同的刺激往往诱导长期抑制（LTD）。先前的研究表明，纹状体LTD的诱导依赖于逆行性内源性大麻素信号传导和CB1大麻素受体的激活。还已知主要内源性CB1受体激动剂之一花生四烯乙醇胺（AEA）的水平在全脑样本发育过程中会升高。在本研究中，我们试图确定AEA的这种发育性增加是否也发生在纹状体组织中，以及AEA水平的升高是否促成了对HFS反应的出生后转变。我们观察到，在以从LTP向LTD转变为特征的出生后时期，纹状体中AEA水平显著升高，但另一种主要内源性大麻素2-花生四烯酸甘油（2-AG）的水平没有升高。此外，在对P12-P14大鼠脑片进行场记录时，在HFS期间应用合成AEA可诱导LTD，而在P16-P34动物的HFS期间阻断CB1受体则导致LTP的表达。然而，用二酰甘油脂肪酶抑制剂四氢脂抑素阻断2-AG合成并没有改变HFS诱导的纹状体LTD。此外，合成CB1激动剂产生的突触抑制在整个发育过程中是相似的。总之，这些发现表明，纹状体AEA在发育过程中的强劲增加可能是HFS诱导的纹状体LTD出现的关键因素。
