Novel Environment and GABA Agonists Alter Event-Related Potentials in N-Methyl-D-aspartate NR1 Hypomorphic and Wild-Type Mice
Novel Environment and GABA Agonists Alter Event-Related Potentials in N-Methyl-D-aspartate NR1 Hypomorphic and Wild-Type Mice
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DOI：
10.1124/jpet.109.150938
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发表时间：
2009-10-01
影响因子：
3.5
通讯作者：
Siegel, Steven J.
中科院分区：
文献类型：
--
作者：
Bodarky, Christina L.;Halene, Tobias B.;Siegel, Steven J.
临床和实验数据表明，N-甲基-D-天冬氨酸受体（NMDAR）介导的多巴胺能通路在精神分裂症的失调。NMDAR介导的异常和对新环境的反应之间的相互作用尚未研究。将表达5 - 10%正常N-甲基-D-天冬氨酸受体亚单位1（NR 1）亚单位[NR 1（neo）（-/-）]的小鼠与野生型同窝小鼠的听觉事件相关电位（ERP）在20 ms（P20）时的正偏转和在40 ms（N40）时的负偏转进行比较。在五个测试阶段内和跨五个测试阶段测试各组的习惯性，在第六个阶段测试新环境。随后，我们研究了GABA（A）阳性变构调节剂（利血平）和GABA（B）受体激动剂（巴氯芬）作为使异常反应正常化的潜在干预措施的作用。在每个习惯日内，P20振幅降低，但N40振幅不降低。尽管在习惯日期间没有振幅或门控变化，但在新环境中P20和N40振幅和门控有所降低。N40基因型间无差异。只有NR 1（neo）（-/-）小鼠在新环境中P20降低。利血平增加野生型小鼠的N40振幅，而巴氯芬增加NR 1（neo）（-/-）小鼠的P20振幅。如之前的出版物所述，NR 1（neo）（-/-）小鼠的ERP模式并不能概括精神分裂症的异常。此外，NR 1表达减少不影响N40习惯化，但在新环境中确实影响P20。因此，在人类研究中，P50（50 ms时的正偏转）而不是N100（100 ms时的负偏转）的模式可能与受试者对不熟悉环境的反应有关。此外，NR 1减少减少GABA（A）受体介导的对ERP的作用，同时引起GABA（B）受体介导的作用增加。未来的研究将检查GABA受体亚单位的变化后，NR 1表达减少。
Clinical and experimental data suggest dysregulation of N-methyl-D-aspartate receptor (NMDAR)-mediated glutamatergic pathways in schizophrenia. The interaction between NMDAR-mediated abnormalities and the response to novel environment has not been studied. Mice expressing 5 to 10% of normal N-methyl-D-aspartate receptor subunit 1 (NR1) subunits [NR1(neo)(-/-)] were compared with wild-type littermates for positive deflection at 20 ms (P20) and negative deflection at 40 ms (N40) auditory event-related potentials (ERPs). Groups were tested for habituation within and across five testing sessions, with novel environment tested during a sixth session. Subsequently, we examined the effects of a GABA(A) positive allosteric modulator (chlordiazepoxide) and a GABA(B) receptor agonist (baclofen) as potential interventions to normalize aberrant responses. There was a reduction in P20, but not N40 amplitude within each habituation day. Although there was no amplitude or gating change across habituation days, there was a reduction in P20 and N40 amplitude and gating in the novel environment. There was no difference between genotypes for N40. Only NR1(neo)(-/-) mice had reduced P20 in the novel environment. Chlordiazepoxide increased N40 amplitude in wild-type mice, whereas baclofen increased P20 amplitude in NR1(neo)(-/-) mice. As noted in previous publications, the pattern of ERPs in NR1(neo)(-/-) mice does not recapitulate abnormalities in schizophrenia. In addition, reduced NR1 expression does not influence N40 habituation but does affect P20 in a novel environment. Thus, the pattern of P50 ( positive deflection at 50 ms) but not N100 (negative deflection at 100 ms) in human studies may relate to subjects' reactions to unfamiliar environments. In addition, NR1 reduction decreased GABA(A) receptor-mediated effects on ERPs while causing increased GABA(B) receptor-mediated effects. Future studies will examine changes in GABA receptor subunits after reductions in NR1 expression.