Rossner S, Schliebs R, Bigl V
Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Germany.
Brain Res. 1995 Oct 23;696(1-2):165-76. doi: 10.1016/0006-8993(95)00844-g.
To study the effect of reduced cortical cholinergic activity on GABAergic and glutamatergic mechanisms in cholinoceptive cortical target regions a novel cholinergic immunotoxin (conjugate of the monoclonal antibody 192IgG against the low-affinity nerve growth factor receptor with the cytotoxic protein saporin) was applied, which specifically and selectively destroys cholinergic cells in rat basal forebrain nuclei. To correlate the responses to cholinergic immunolesion in cholinoceptive cortical target regions with cholinergic hypoactivity, quantitative receptor autoradiography to measure NMDA, AMPA and kainate glutamate receptor subtypes, GABAA and benzodiazepine receptors as well as choline uptake sites, and histochemistry to estimate acetylcholinesterase activity were performed in adjacent brain sections. One week after a single intraventricular injection of 4 micrograms of 192IgG-saporin, NMDA receptor binding was markedly reduced in cortical regions displaying a reduced activity of acetylcholinesterase and high-affinity choline uptake sites as a consequence of cholinergic lesion, whereas AMPA and kainate binding sites were significantly increased in these regions. Muscimol binding to GABAA receptors was increased in the caudal portions of frontal and parietal cortices as well as occipital and temporal cortex as compared to the corresponding brain regions from vehicle-injected control rats. Binding levels of benzodiazepine receptors were not affected by the lesion in any of the cortical regions studied. The differential changes in glutamate and GABA receptor subtypes following cholinergic immunolesion might be regarded as the consequence of a cortical reorganization compensating for the reduced cholinergic presynaptic input. The data further suggest that presynaptic cortical cholinergic deficits might affect both glutamatergic and GABAergic functions with different intensity and different directions.
为研究皮质胆碱能活性降低对胆碱能感受性皮质靶区GABA能和谷氨酸能机制的影响，应用了一种新型胆碱能免疫毒素（抗低亲和力神经生长因子受体的单克隆抗体192IgG与细胞毒性蛋白皂草素的偶联物），该毒素能特异性、选择性地破坏大鼠基底前脑核中的胆碱能细胞。为了将胆碱能感受性皮质靶区对胆碱能免疫损伤的反应与胆碱能功能减退相关联，在相邻脑切片上进行了定量受体放射自显影以测量NMDA、AMPA和海人藻酸谷氨酸受体亚型、GABAA和苯二氮䓬受体以及胆碱摄取位点，并进行了组织化学以评估乙酰胆碱酯酶活性。在脑室内单次注射4微克192IgG - 皂草素一周后，由于胆碱能损伤，在显示乙酰胆碱酯酶活性降低和高亲和力胆碱摄取位点减少的皮质区域，NMDA受体结合显著降低，而在这些区域AMPA和海人藻酸结合位点显著增加。与注射赋形剂的对照大鼠相应脑区相比，蝇蕈醇与GABAA受体的结合在额叶和顶叶皮质以及枕叶和颞叶皮质的尾部增加。在所研究的任何皮质区域，苯二氮䓬受体的结合水平均未受损伤影响。胆碱能免疫损伤后谷氨酸和GABA受体亚型的差异变化可能被视为皮质重组以补偿胆碱能突触前输入减少的结果。数据进一步表明，突触前皮质胆碱能缺陷可能以不同强度和不同方向影响谷氨酸能和GABA能功能。
