McCoy Portia A, McMahon Lori L
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
J Neurophysiol. 2007 Oct;98(4):1862-70. doi: 10.1152/jn.00510.2007. Epub 2007 Jul 18.
Intact cholinergic innervation of visual cortex is critical for normal processing of visual information and for spatial memory acquisition and retention. However, a complete description of the mechanisms by which the cholinergic system modifies synaptic function in visual cortex is lacking. Previously it was shown that activation of the m1 subtype of muscarinic receptor induces an activity-dependent and partially N-methyl-d-aspartate receptor (NMDAR)-dependent long-term depression (LTD) at layer 4-layer 2/3 synapses in rat visual cortex slices in vitro. The cellular mechanisms downstream of the Galphaq coupled m1 receptor required for induction of this LTD (which we term mLTD) are currently unknown. Here, we confirm a role for m1 receptors in mLTD induction and use a series of pharmacological tools to study the signaling molecules downstream of m1 receptor activation in mLTD induction. We found that mLTD is prevented by inhibitors of L-type Ca(2+) channels, the Src kinase family, and the mitogen-activated kinase/extracellular kinase. mLTD is also partially dependent on phospholipase C but is unaffected by blocking protein kinase C. mLTD expression can be long-lasting (>2 h) and its long-term maintenance requires translation. Thus we report the signaling mechanisms underlying induction of an m1 receptor-dependent LTD in visual cortex and the requirement of protein synthesis for long-term expression. This plasticity could be a mechanism by which the cholinergic system modifies glutamatergic synapse function to permit normal visual system processing required for cognition.
视觉皮层完整的胆碱能神经支配对于视觉信息的正常处理以及空间记忆的获取和保持至关重要。然而，目前尚缺乏对胆碱能系统调节视觉皮层突触功能机制的完整描述。此前研究表明，毒蕈碱受体m1亚型的激活可在体外大鼠视觉皮层切片的第4层至第2/3层突触处诱导一种活性依赖且部分依赖N-甲基-D-天冬氨酸受体（NMDAR）的长时程抑制（LTD）。目前尚不清楚诱导这种LTD（我们称之为mLTD）所需的Gαq偶联m1受体下游的细胞机制。在此，我们证实了m1受体在mLTD诱导中的作用，并使用一系列药理学工具来研究mLTD诱导中m1受体激活下游的信号分子。我们发现，L型Ca(2+)通道抑制剂、Src激酶家族抑制剂和丝裂原活化蛋白激酶/细胞外信号调节激酶可阻止mLTD。mLTD也部分依赖于磷脂酶C，但不受蛋白激酶C阻断的影响。mLTD的表达可持续较长时间（>2小时），其长期维持需要翻译。因此，我们报告了视觉皮层中m1受体依赖性LTD诱导的信号机制以及长期表达对蛋白质合成的需求。这种可塑性可能是胆碱能系统调节谷氨酸能突触功能以实现认知所需正常视觉系统处理的一种机制。
