Molecularmechanism of motor learning

为了探讨运动学习的分子机制，我们分析了谷氨酸受体亚单位基因敲除(KO)小鼠的眨眼条件反射。我们使用了小脑浦肯野细胞特异性GluRδ2KO和NMDA型GluRε1KO小鼠。1)利用条件刺激(CS)和非条件刺激(US)之间的不同时间间隔，对GLURδ2 KO小鼠进行了眨眼条件反射实验。在CS与US在时间上重叠的延迟范式中，Glurδ2 KO小鼠表现出严重的学习障碍。相比之下，GLURδ2 KO小鼠很好地学习了CS和US之间没有时间重叠的范式。由于Glurδ2 KO小鼠缺乏小脑LTD，这些结果表明当CS-US存在时间重叠时，Glurδ2和LTD对运动学习是必不可少的，这表明眨眼条件下的小脑底物可能会改变，这取决于CS和US的时间重叠。2)NMDA型Glurε1 KO小鼠在眨眼条件下表现出严重的学习障碍，CS和US之间存在较长的踪迹间隔。相比之下，这些小鼠在延迟和短轨迹范例中表现出较慢的学习速度。3)我们还分析了NMDA型GluRε1 KO、GLURε2 KO、GLURε3 KO和GLURε4 KO小鼠的声惊厥反应。Glurε2异种KO小鼠表现出ASR的增强。另一方面，其他NMDA型GluRε亚基的杂合性和纯合性突变对ASR没有或只有很小的影响。我们认为GluRε2亚基在ASR的调节中起着明显的作用。

To investigate the molecular mechanism of motor learning, we have analyzed the eyeblink conditioning in glutamate receptor (GluR) subunit gene knockout (KO) mice. We have used cerebellar Purkinje cell-specific GluRδ2 KO and NMDA-type GluRε1 KO mice. We have obtained following results.1) We conducted the eyeblink conditioning with GluRδ2 KO mice, using various temporal intervals between the conditioned stimulus (CS) and unconditioned stimulus (US). In the delay paradigm in which the CS overlapped temporally with US, GluRδ2 KO mice exhibited severe learning impairment. In contrast, GluRδ2 KO mice learned well the paradigm in which no temporal overlap between the CS and US. Because the GluRδ2 KO mice have deficient in cerebellar LTD, these results indicates the GluRδ2 and LTD are essential for motor learning when there is CS-US temporal overlap, suggesting that the cerebellar substrates underlying eyeblink conditioning may change, depending on the temporal overlap of the CS and US.2) The NMDA-type GluRε1 KO mice exhibited sever learning impairment in eyeblink conditioning with a long trace interval between the CS and US. In contrast, these mice showed a little slow learning in the delay and short trace paradigms. These results indicate that the NMDA-type GluRε1 is essential for long-trace interval eyeblink conditioning.3) We have also analyzed the acoustic startle response (ASR) of NMDA-type GluRε1 KO, GluRε2 KO, GluRε3 KO and GluRε4 KO mice. The GluRε2 hetero KO mice showed the enhancement of ASR. On the other hand, heterozygous and homozygous mutation of the other NMDA-type GluRε subunits exerted no, or only small effects on ASR. We suggest that the GluRε2 subunit play a distinct role in the regulation of the ASR.