P42/44丝裂原活化蛋白激酶抑制剂PD98059可减弱体外培养的大鼠齿状回中多种形式的突触可塑性。

P42/44 MAP kinase inhibitor PD98059 attenuates multiple forms of synaptic plasticity in rat dentate gyrus in vitro.

作者信息

Coogan A N, O'Leary D M, O'Connor J J

机构信息

Department of Human Anatomy and Physiology, University College, Earlsfort Terrace, Dublin 2, Ireland.

出版信息

J Neurophysiol. 1999 Jan;81(1):103-10. doi: 10.1152/jn.1999.81.1.103.

DOI:10.1152/jn.1999.81.1.103

PMID:9914271

Abstract

The effects of the specific p42/44 mitogen-activated protein (MAP) kinase cascade inhibitor, PD98059, were investigated on three types of long-term potentiation (LTP) in the medial perforant path of the rat dentate gyrus in vitro: LTP induced by 1) high-frequency stimulation (HFS-LTP), 2) application for 10 min of the K+ channel blocker, tetraethylammonium chloride (TEA-LTP), and 3) application of the metabotropic glutamate receptor (mGluR) agonist (S)-dihydrophenylglycine (S-DHPG) for 2 min (DHPG-LTP). Bath perfusion of PD98059 (50 microM) for 1 h inhibited HFS-LTP (111 +/- 5%, mean +/- SE, at 90 min posttetanus in test slices compared with 144 +/- 5% in control slices; n = 6-7). Concentrations of 10 and 20 microM PD98059 had no effect on HFS-LTP (n = 6). PD98059 (50 microM) had no effect on the isolated N-methyl--aspartate excitatory postsynaptic potential (NMDA-EPSP) or on the maintenance phase of HFS-LTP. PD98059 (50 microM) did not affect paired-pulse depression (PPD; interstimulus intervals of 10 and 100 ms) of synaptic transmission as is typically observed in the medial perforant path of the dentate gyrus. Bath application of (S)-DHPG (40 microM) for 2 min gave rise to a potentiation of the EPSPs slope (148 +/- 4% at 1 h post-DHPG wash out; n = 5). Pretreatment of slices with PD98059 (50 microM) inhibited the DHPG-LTP (98 +/- 3% at 1 h post-DHPG wash out; n = 5). The TEA-LTP (125 +/- 4% at 1 h post-TEA wash out; n = 6) was found to be both -2-amino-5-phosphonopentanoic acid (-AP5; 100 microM) and nifedipine (20 microM) independent. However, the T type voltage-dependent calcium-channel blocker, NiCl2 (50 microM), completely inhibited the observed potentiation. The mGluR receptor antagonist alpha-methyl-4-carboxy-phenyl glycine (MCPG; 100 microM) and PD98059 (50 microM) caused a complete block of the TEA-LTP. These data show for the first time an involvement of the p42/44 MAP kinase in the induction and expression of both an NMDA-dependent and two forms of NMDA-independent LTP in the dentate gyrus.

摘要

研究了特异性p42/44丝裂原活化蛋白（MAP）激酶级联抑制剂PD98059对体外大鼠齿状回内侧穿通路径中三种长时程增强（LTP）的影响：1）高频刺激诱导的LTP（HFS-LTP）；2）应用钾离子通道阻滞剂氯化四乙铵10分钟诱导的LTP（TEA-LTP）；3）应用代谢型谷氨酸受体（mGluR）激动剂（S）-二氢苯甘氨酸（S-DHPG）2分钟诱导的LTP（DHPG-LTP）。用50μM的PD98059进行浴灌流1小时可抑制HFS-LTP（强直刺激后90分钟时，测试切片中为111±5%，平均值±标准误，而对照切片中为144±5%；n = 6 - 7）。10μM和20μM的PD98059浓度对HFS-LTP无影响（n = 6）。50μM的PD98059对分离的N-甲基-D-天冬氨酸兴奋性突触后电位（NMDA-EPSP）或HFS-LTP的维持阶段无影响。50μM的PD98059不影响齿状回内侧穿通路径中通常观察到的突触传递的双脉冲抑制（PPD；刺激间隔为10和100毫秒）。用40μM的（S）-DHPG进行2分钟的浴灌流可使兴奋性突触后电位斜率增强（DHPG洗脱后1小时为148±4%；n = 5）。用50μM的PD98059预处理切片可抑制DHPG-LTP（DHPG洗脱后1小时为98±3%；n = 5）。发现TEA-LTP（TEA洗脱后1小时为125±4%；n = 6）既不依赖于-2-氨基-5-磷酸戊酸（-AP5；100μM）也不依赖于硝苯地平（20μM）。然而，T型电压依赖性钙通道阻滞剂NiCl2（50μM）完全抑制了观察到的增强作用。mGluR受体拮抗剂α-甲基-4-羧基苯甘氨酸（MCPG；100μM）和PD98059（50μM）可完全阻断TEA-LTP。这些数据首次表明p42/44 MAP激酶参与了齿状回中NMDA依赖性和两种形式的NMDA非依赖性LTP的诱导和表达。