Alkondon M, Pereira E F, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore 21201, USA.
J Pharmacol Exp Ther. 1996 Dec;279(3):1491-506.
To assess the density and distribution of functional nicotinic acetylcholine receptors (nAChRs) and gamma-aminobutyric acid (GABA) receptors on hippocampal neurons, we have combined infrared videomicroscopy with a nanorobotic micromanipulator system and studied the receptor-mediated currents by using the whole-cell patch-clamp technique. Acetylcholine or GABA was applied by pressure ejection onto a small segment of either cell soma or dendrite, and the resulting current was measured in cultured hippocampal neurons by using a whole-cell pipette positioned at the cell soma. Type IA nicotinic currents, sensitive to blockade by methyllycaconitine (1 nM) and alpha-bungarotoxin and associated with alpha 7-subunit-containing nAChRs, type II currents, sensitive to blockade by dihydro-beta-erythroidine (100 nM) subserved by alpha 4 beta 2 nAChRs, and GABA-mediated currents were evoked when the agonists were applied to either cell soma or the dendrites. Analysis of the current amplitude with respect to the membrane area covered by the applied agonist provided an estimation of the receptor density along the somato-dendritic axis of the hippocampal neurons. Such analysis revealed: 1) a nonuniform distribution for the receptor types studied; 2) a higher density of nAChR and GABA receptors at the dendrites than at the soma; and 3) an increasing density for both nAChR subtypes with distance from the center of the cell soma, but increasing and then decreasing density for the GABA receptor. Exposure of cultured hippocampal neurons to colchicine (100 nM for 3 days) produced a dramatic reduction in the dendritic branching, and this morphological feature was associated with a significant decrease in the receptor density, such an effect being more prominent for nAChRs than for GABA receptors. Given the high Ca+2 permeability of nAChRs, the dendritic localization of nAChRs suggest that they are involved in modulating the synaptic efficacy at the level of the dendrites.
为了评估海马神经元上功能性烟碱型乙酰胆碱受体(nAChRs)和γ-氨基丁酸(GABA)受体的密度及分布,我们将红外视频显微镜与纳米机器人微操纵系统相结合,并使用全细胞膜片钳技术研究受体介导的电流。通过压力喷射将乙酰胆碱或GABA施加到细胞体或树突的一小段上,然后使用位于细胞体处的全细胞膜片吸管测量培养的海马神经元中产生的电流。对甲基lycaconitine(1 nM)和α-银环蛇毒素阻断敏感且与含α7亚基的nAChRs相关的IA型烟碱电流、对二氢β-刺桐啶(100 nM)阻断敏感且由α4β2 nAChRs介导的II型电流以及GABA介导的电流,在激动剂施加到细胞体或树突时均可诱发。分析电流幅度相对于施加激动剂覆盖的膜面积,可估算海马神经元体-树突轴上的受体密度。这种分析揭示:1)所研究的受体类型分布不均匀;2)树突处的nAChR和GABA受体密度高于细胞体;3)两种nAChR亚型的密度均随距细胞体中心距离的增加而增加,但GABA受体的密度先增加后降低。将培养的海马神经元暴露于秋水仙碱(100 nM,持续3天)会导致树突分支显著减少,这种形态学特征与受体密度的显著降低相关,nAChRs的这种效应比GABA受体更明显。鉴于nAChRs具有高Ca+2通透性,nAChRs在树突上的定位表明它们参与调节树突水平的突触效能。