Kainate receptor subunits in the mouse cerebellum

神经元之间的连接(称为突触)是以对哺乳动物大脑正常功能至关重要的方式进行调节的。我的研究计划的长期目标是识别和描述涉及小鼠小脑突触调制的机制-大脑的一个区域，对运动协调和运动学习至关重要。谷氨酸是中枢神经系统中含量最丰富的兴奋性神经递质。谷氨酸可激活3类主要的离子通透性受体：AMPA、NMDA和海人藻酸受体。虽然AMPA和NMDA受体的特性很好，但对海人酸类谷氨酸受体的了解相对较少。最近的证据表明，红藻氨酸受体可能通过调节谷氨酸的释放在神经传递的调节中发挥重要作用。我的实验室最近的实验表明，在小脑中，红藻氨酸受体通过增加一个突触的谷氨酸释放来加强神经传递，但通过减少另一个突触的释放来削弱神经传递。这两个突触的调节对于正常的运动协调和运动学习至关重要。我的研究计划的主要目标是确定海人酸受体如何以不同的方式调节小脑中谷氨酸的释放，以及这种调制对运动行为是如何重要的。具体地说，我将使用缺乏五个海人酸受体亚基中的每一个的基因工程小鼠来测试这样一个假设，即增加释放的海人酸受体由不同的亚基组成，而减少释放的海人酸受体则由不同的亚基组成。然后，我将使用基于视频的步态分析和前庭-眼睛反射的眼球运动来测试这些小鼠在运动协调和运动学习方面的细微差异。这项研究的结果将为深入了解红藻氨酸受体的不同亚单位组成如何调节大脑中兴奋和抑制之间的平衡，以及如何在小鼠小脑中产生习得运动行为的协调提供洞察。

Connections between neurons (called synapses) are modulated in ways that are critical for the normal functioning of the mammalian brain. The long-term goal of my research program is to identify and characterize the mechanisms that are involved in synaptic modulation in the mouse cerebellum - an area of the brain that is critical for motor co-ordination and motor learning. Glutamate is the most abundant excitatory neurotransmitter found in the central nervous system. Glutamate can activate 3 main classes of ion permeable receptors: AMPA, NMDA and kainate receptors. Although AMPA and NMDA receptors are well characterized, relatively little is known about the kainate class of glutamate receptors. Recent evidence suggests that kainate receptors may play an important role in the modulation of neurotransmission by regulating glutamate release. Recent experiments in my laboratory have shown that in the cerebellum, kainate receptors strengthen neurotransmission by increasing glutamate release at one synapse, but weaken neurotransmission by decreasing release at another synapse. Modulation of both synapses is critical for normal motor co-ordination and motor learning. The main objective of my research program is to determine how kainate receptors differentially modulate glutamate release in the cerebellum and how this modulation is important for motor behaviour.  Specifically, I will use genetically engineered mice that lack one of each of the five kainate receptor subunits to test the hypothesis that kainate receptors that increase release are made up of different subunits then kainate receptors that decrease release. I will then test these mice for subtle differences in motor co-ordination and motor learning using video-based gait analysis and eye movements in the vestibular-ocular reflex . The results from this study will provide insight into how the differential subunit composition of kainate receptors regulates the balance between excitation and inhibition in the brain and how co-ordination of learned motor behaviour is generated in the mouse cerebellum.