Ling Douglas S F, Benardo Larry S
Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, NY 11203,
Cereb Cortex. 2005 Jul;15(7):921-8. doi: 10.1093/cercor/bhh191. Epub 2004 Sep 30.
It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation-inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABA(A) receptor responses in pyramidal cells. This suggests that the therapeutic actions of nootropic agents may be partly mediated through enhanced cortical GABAergic inhibition, and not solely through the direct modification of excitation, as previously thought.
人们普遍认为,促智药(认知增强剂)主要通过对α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(AMPARs)进行正向调节,增强皮质回路中的兴奋性突触传递,从而产生治疗效果。然而,γ-氨基丁酸(GABA)介导的抑制作用对认知也至关重要,增强GABA功能对认知障碍同样可能具有治疗作用。促智药是否也能通过这样的机制发挥作用呢?为了解决这个问题,我们研究了促智药对体感皮层急性切片中V层锥体细胞记录到 的兴奋性和抑制性突触后电流(EPSCs和IPSCs)的影响。阿尼西坦是一种AMPA/海人藻酸受体的正向调节剂,它增加了诱发EPSCs的峰值幅度以及多突触快速IPSCs的幅度和持续时间,表现为IPSCs携带的总电荷量增加。结果,总电荷量的EPSC/IPSC比值降低,这代表兴奋-抑制平衡向有利于抑制的方向转变。阿尼西坦不影响在存在兴奋性氨基酸受体拮抗剂时记录到的单突触IPSCs(单突触抑制性突触后电流,mono-IPSCs)的大小,也不影响在存在河豚毒素时记录到的微小IPSCs(微小抑制性突触后电流,mIPSCs)的大小。然而,单突触抑制性突触后电流和微小抑制性突触后电流的持续时间都延长了,这表明阿尼西坦也直接调节GABA能传递。环噻嗪是一种AMPAR功能的优先调节剂,与阿尼西坦类似,它增强了多突触IPSCs的幅度和持续时间,但不影响单突触抑制性突触后电流。伴刀豆球蛋白A是一种海人藻酸受体调节剂,对EPSCs或IPSCs几乎没有影响,这表明海人藻酸受体活性没有作用。这些发现表明,AMPAR调节剂增强了新皮质锥体细胞中的抑制作用,最有可能是通过改变突触连接的中间神经元上AMPARs的动力学,也可能是通过调节锥体细胞中的GABA(A)受体反应。这表明促智药的治疗作用可能部分是通过增强皮质GABA能抑制介导的,而不仅仅是如之前所认为的那样通过直接改变兴奋性来实现。