Actions of proline at receptors and synapses

大脑处理氨基酸脯氨酸的障碍与多种神经系统和 行为障碍，包括精神分裂症、自闭症、癫痫、智力残疾和抑郁症。虽然 脯氨酸被认为是一种候选的神经递质，证明了神经递质中的脯氨酸能成分。 synaptic一直缺乏。脯氨酸被认为是介导其行动，部分，通过激活离子型谷氨酸 受体，其介导中枢神经系统中的大多数突触传递。然而， 谷氨酸受体上的脯氨酸和突触传递还不清楚。我们假设 离子型谷氨酸受体的脯氨酸敏感性随亚基组成而变化。此外，我们建议， 脯氨酸能传递可以通过药理学探测神经元之间的传递来证明， 表达SLC6A7，高亲和力脯氨酸转运蛋白，负责大部分突触脯氨酸摄取，和 它的突触后伙伴。我们将结合电生理学，分子学，免疫细胞化学， 和成像方法，我们将研究：1）药理学概况的脯氨酸在重组离子型 具有不同亚基组成的谷氨酸受体; 2）作为靶点的首选海马细胞类型 以及3）突触诱发的脯氨酸积累如何形成突触能神经元 传输总的来说，这些研究将填补我们关于脯氨酸作用的知识的主要空白， 在谷氨酸受体和突触上，脯氨酸能传递可能发生。

Disturbances in brain handling of the amino acid proline are linked to a wide variety neurological and behavioral disorders including schizophrenia, autism, epilepsy, intellectual disability, and depression. Although proline has been suggested to be a candidate neurotransmitter, a demonstration of a prolinergic component of synaptic has been lacking. Proline is thought to mediate its action, in part, via activation of ionotropic glutamate receptors, which mediate the majority of synaptic transmission in the central nervous system. Yet, the actions of proline at glutamate receptors and synaptic transmission are not well understood. We hypothesize that the proline sensitivity of ionotropic glutamate receptors varies with subunit composition. Moreover, we propose that prolinergic transmission can be demonstrated by pharmacologically probing transmission between neurons that express SLC6A7, the high-affinity proline transporter responsible for a majority of synaptic proline uptake, and its postsynaptic partners. We will use a combination of electrophysiological, molecular, immunocytochemical, and imaging methods we will examine: 1) the pharmacological profile of proline at recombinant ionotropic glutamate receptors with distinct subunit compositions; 2) the preferred hippocampal cell types that are targets of putative prolinergic neurons; and 3) the how synaptically evoked proline accumulations shape glutamatergic transmission. Collectively, these studies will fill in major gaps in our knowledge regarding the actions of proline at glutamate receptors and synapses where prolinergic transmission likely occurs.