Virgili M, Facchinetti F, Sparapani M, Tregnago M, Lucchi R, Dall'Olio R, Gandolfi O, Contestabile A
Department of Biology, University of Bologna, Italy.
Neurosci Lett. 1998 Dec 11;258(1):1-4. doi: 10.1016/s0304-3940(98)00742-3.
Pharmacological blockade of the (NMDA) receptor at critical stages of brain development may have long-lasting effects on brain chemistry and on animal behavior. We report here experiments in which the competitive NMDA receptor antagonist CGP 39551 was administered to rat pups from postnatal day 7 (P7) to P18. The stage of treatment was selected to primarily target the cerebellum, whose granule cells undergo post-mitotic migration and establishment of synaptic connections during this period. We focused our study on the long-term consequences of CGP 39551 treatment on the neuronal isoform of nitric oxide synthase (nNOS) since nNOS is highly expressed in the cerebellum and it is functionally linked to the NMDA receptor. Treated rats exhibited a long-lasting (up to P70) decrease in the intensity of nNOS immunocytochemical staining in the cerebellar cortex accompanied by a decrement of calcium-dependent NOS catalytic activity. A comparable decrease of enzyme activity was measured in the cerebral cortex, but not in the hippocampus, of adult rats. Other neurochemical markers (glutamatergic, gabaergic, purinergic) and glutamine synthetase were unchanged, while a cholinergic marker was slightly increased in the cerebellum of CGP 39551 treated animals. Taken together these data show that blockade of NMDA receptor during the critical period of formation and stabilization of neuronal circuits preferentially affects long-term nNOS expression and catalytic activity in the cerebellum.
在大脑发育的关键阶段对（NMDA）受体进行药理学阻断可能会对大脑化学和动物行为产生长期影响。我们在此报告了一些实验，其中从出生后第7天（P7）至P18给幼鼠施用竞争性NMDA受体拮抗剂CGP 39551。选择该治疗阶段主要是针对小脑，在此期间小脑的颗粒细胞经历有丝分裂后的迁移和突触连接的建立。我们将研究重点放在CGP 39551治疗对一氧化氮合酶（nNOS）神经元同工型的长期影响上，因为nNOS在小脑中高度表达且在功能上与NMDA受体相关联。经治疗的大鼠在小脑皮质中nNOS免疫细胞化学染色强度出现长期（直至P70）下降，同时钙依赖性NOS催化活性降低。在成年大鼠的大脑皮质中测得酶活性有类似下降，但在海马体中未出现。其他神经化学标记物（谷氨酸能、γ-氨基丁酸能、嘌呤能）和谷氨酰胺合成酶未发生变化，而在CGP 39551治疗的动物的小脑中胆碱能标记物略有增加。综合这些数据表明，在神经元回路形成和稳定的关键时期阻断NMDA受体优先影响小脑中nNOS的长期表达和催化活性。
