Targeted Disruption of L-Proline Transporter Gene by Homolgous Recombination

神经生物学中许多最激动人心的技术进步都来自基因工程领域。现在有可能选择性地“敲除”单个基因，并检查它们对行为的影响。被称为“基因敲除小鼠”的老鼠，已经被用来探测学习和记忆、温度适应和许多其他行为背后的神经回路。它们为阐明基因和行为之间长期神秘的联系提供了高度选择性的探针。Fremeau博士最近克隆了脯氨酸高亲和膜转运体的基因。脯氨酸的吸收系统存在于谷氨酰胺能神经末梢的选择性群体中，这表明脯氨酸是一种新的神经递质，在某种程度上改变了谷氨酰胺能的传递。由于谷氨酸是大脑皮层的主要递质，并参与神经可塑性的机制，因此确定脯氨酸在谷氨酸能功能中的作用显然是非常有意义的。美国国家科学基金会探索性研究（SGER）小额赠款将使Fremeau博士有机会使用基因工程技术来解决这个问题。他将尝试一项高风险/高增益的任务，即制造一种缺乏这种膜成分的敲除小鼠。如果他成功了，就有可能确定脯氨酸神经传递在行为发展中的作用。SGER就是为这类研究而设计的，很少有其他的资助机制来支持那些没有相当确定回报的研究

Many of the most exciting technical advances in neurobiology have come from the field of genetic engineering. It is now possible to selectively "knock out" single genes and examine their effect on behavior. Knock-out mice, as they are called, have been used to probe the circuits underlying learning and memory, temperature adaptation, and many other behaviors. They provide highly selective probes for elucidating the long mysterious connection between genes and behavior. Dr. Fremeau has recently cloned the gene for a high-affinity membrane transporter for proline. The fact that these uptake systems for proline are found in selective populations of glutaminergic nerve terminals suggests that proline is a novel neurotransmitter which modifies glutaminergic transmission in some way. Since glutamate is a major transmitter in cerebral cortex and involved in mechanisms of neuroplasticity, it is obviously of great interest to determine proline's role in glutaminergic function. This NSF small grant for exploratory research (SGER) will give Dr. Fremeau the chance to use genetic engineering techniques to solve this problem. He will attempt the high-risk/high gain task of producing a knock out mouse that lacks this membrane component. If he succeeds it will be possible to determine the role that proline neurotransmission plays in the development of behavior. This is the kind of research for which the SGER was designed for there are few other funding mechanisms for supporting research that does not have a fairly assured payoff.***//