Bortolotto Z A, Collingridge G L
Department of Pharmacology, Medical School, University of Birmingham, Edgbaston, U.K.
Neuropharmacology. 1995 Aug;34(8):1003-14. doi: 10.1016/0028-3908(95)00054-a.
We have reported previously that transient application of a specific metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD) can induce a slow-onset form of long-term potentiation (LTP) of synaptic transmission in the CA1 region of rat hippocampal slices [Bortolotto Z. A. and Collingridge G. L. (1993) Neuropharmacology 32, 1-9]. Here we have investigated further the mechanisms involved in the induction and expression of ACPD-induced LTP. Unless otherwise stated, field excitatory postsynaptic potentials (EPSPs) were recorded in stratum radiatum in response to low frequency (0.033 Hz stimulation) of the Schaffer collateral-commissural pathway and 10 microM ACPD was added for 20 min to the perfusate. ACPD-induced LTP was still observed following blockade of GABAA receptor-mediated synaptic inhibition using picrotoxin (50 microM) and was not the result of a change in the presynaptic fibre volley. Intracellular recording from area CA1 revealed an increase in the size of the EPSP but no associated change in membrane potential or input resistance. However, ACPD-induced potentiation was never seen when intracellular electrodes contained the Ca(2+)-chelating agent 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA; 0.5 M). In area CA3, ACPD elicited a slow-onset LTP of the intracellularly recorded EPSP, evoked by stimulation of associational fibres. In contrast to area CA1, 10 microM ACPD depolarized CA3 neurones. Unlike certain other forms of tetanus- and chemically-induced potentiation, ACPD-induced LTP was not affected by the L-type Ca2+ channel antagonist nimodipine (50 microM). It was, however, prevented by delivering low frequency stimulation (900 shocks at 1 Hz) immediately following termination of the application of ACPD; an effect which was inhibited by the specific N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (AP5; 50 microM). ACPD failed to induce LTP of pharmacologically-isolated NMDA receptor-mediated EPSPs. The induction of ACPD-induced LTP was blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), in a reversible manner. In slices in which area CA3 had been removed ACPD failed to induce LTP when applied alone or together with AMPA. However, a slow-onset form of LTP was induced, in slices lacking area CA3, when a tetanus (100 Hz, 1 sec) was delivered in the presence of ACPD and 50 microM AP5 (the latter applied to prevent conventional tetanus-induced LTP). ACPD-induced LTP was associated with a parallel increase in the sensitivity of CA1 neurones to AMPA. Considered together, these data suggest that ACPD-induced LTP is due to a direct increase in the AMPA receptor-mediated synaptic conductance and involves postsynaptic induction and expression mechanisms.
我们之前报道过，短暂应用特定的代谢型谷氨酸受体（mGluR）激动剂（1S,3R）-1-氨基环戊烷-1,3-二羧酸（ACPD）可在大鼠海马切片CA1区诱导一种突触传递的慢发性长时程增强（LTP）形式[博托洛托·扎·A.和科林格里奇·G. L.（1993年）《神经药理学》32卷，1 - 9页]。在此，我们进一步研究了ACPD诱导的LTP的诱导和表达机制。除非另有说明，在辐射层记录场兴奋性突触后电位（EPSP），以响应Schaffer侧支-连合通路的低频（0.033 Hz刺激），并向灌流液中添加10微摩尔ACPD 20分钟。使用印防己毒素（50微摩尔）阻断GABAA受体介导的突触抑制后，仍可观察到ACPD诱导的LTP，且其并非突触前纤维群峰电位变化的结果。来自CA1区的细胞内记录显示EPSP大小增加，但膜电位或输入电阻无相关变化。然而，当细胞内电极含有钙螯合剂1,2-双（2-氨基苯氧基）乙烷-N,N,N',N'-四乙酸（BAPTA；0.5 M）时，从未观察到ACPD诱导的增强。在CA3区，ACPD通过刺激联合纤维诱发细胞内记录的EPSP的慢发性LTP。与CA1区不同，10微摩尔ACPD使CA3神经元去极化。与某些其他形式的强直刺激和化学诱导的增强不同，ACPD诱导的LTP不受L型钙通道拮抗剂尼莫地平（50微摩尔）的影响。然而，在ACPD应用终止后立即给予低频刺激（1赫兹，900次电击）可阻止其发生；该效应被特异性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂D-2-氨基-5-膦酰戊酸（AP5；50微摩尔）抑制。ACPD未能诱导药理学分离的NMDA受体介导的EPSP的LTP。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体拮抗剂6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）以可逆方式阻断ACPD诱导的LTP的诱导。在去除CA3区的切片中，单独应用ACPD或与AMPA一起应用时均未能诱导LTP。然而，在缺乏CA3区的切片中，当在ACPD和50微摩尔AP5（后者用于防止传统强直刺激诱导的LTP）存在的情况下给予强直刺激（100赫兹，1秒）时，可诱导一种慢发性LTP形式。ACPD诱导的LTP与CA1神经元对AMPA的敏感性平行增加相关。综合考虑，这些数据表明ACPD诱导的LTP是由于AMPA受体介导的突触电导直接增加，且涉及突触后诱导和表达机制。
