The role of neonatal kainate receptors in developing hippocampal circuits.

新生儿红藻氨酸受体在海马回路发育中的作用。

• 批准号: 8609086
• 负责人: Anis Contractor
• 金额: $ 19.12万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609086
• 关键词: Address; Affect; Autistic Disorder; Biological Assay; Bipolar Disorder; Brain; Dendrites; Development; Developmental Process; Disease; Epigenetic Process; Epilepsy; Gated Ion Channel; Glutamates; Hippocampus (Brain); In Vitro; Kainic Acid Receptors; Knockout Mice; Knowledge; Mediating; Mental Depression; Mental Retardation; Mus; Mutant Strains Mice; Neonatal; Neurons; Neurotransmitter Receptor; Plant Roots; Play; Potassium Channel; Process; Property; RNA Editing; Regulation; Role; Schizophrenia; Signal Pathway; Signal Transduction; Source; Synapses; Synaptic Transmission; Testing; Transcript; base; neonate; neural circuit; neurodevelopment; neuropsychiatry; novel; postnatal; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): Spontaneous electrical activity in the neonate is critical to synaptic refinement and epigenetic processes of neural development. Network bursts that contribute to circuit development are a hallmark of the young hippocampus when neurons are more excitable than in the mature CNS. Spontaneous activity of CA3 neurons in the hippocampus is largely dependent on intrinsic conductances that underlie the after hyperpolarization potential (AHP). This conductance can be dynamically regulated by a class of glutamate-gated receptors, kainate receptors (KARs), which have been prominently associated with neurodevelopmental and neuropsychiatric disorders. Neonatal KARs are potentially a key regulator of the AHP in the developing hippocampus~ however it is not known whether certain properties of neonatal KARs, (e.g. their editing status, their linkage to particular signaling pathways, or how they are activated), make them more likely to play this role in neonate versus the mature hippocampus. Here we propose to address these fundamental questions by determining how neonatal KARs produce long-lasting inhibition of AHPs to regulate excitability of hippocampal neurons. Overall these studies will define a role for neonatal KARs in regulating activity in the hippocampus and will address a gap in our knowledge about their specialized role in developing circuits. In Aim 1 we will use in vitro electrophysiological recording to determine whether KARs play a role in regulating the spontaneous activity of CA3 hippocampal neurons. Recordings will be made from KAR knockout mice and mutant mice that express only the mature form of the receptor to determine how these manipulations affect spontaneous bursting of hippocampal neurons. KARs are predominantly extrasynaptic during early development raising the question of how they might be activated. In Aim 2 we hypothesize that extrasynaptic KARs can be activated by ambient glutamate, and this form of tonic signaling is critical to their specialized function in the neonate. Finally, in Aim 3 we will determine how extrasynaptic hippocampal KARs might be activated in the neonate. We will test two specific hypotheses (i) that neonatal KARs are activated by synaptic glutamate (e.g. through spillover) or (ii) by glutamate released from a non-conventional mechanism (e.g. gliotransmission). Together these studies will determine the mechanism by which neonatal KARs regulate excitability in the developing hippocampus. Altered developmental processes in the neonate could ultimately contribute to some of the neurodevelopmental and neuropsychiatric disorders that are associated with KARs such as mental retardation, autism, schizophrenia, bipolar disorder, and epilepsy.

描述（由申请人提供）：新生儿的自发电活动对于神经发育的突触细化和表观遗传过程至关重要。当神经元比成熟的中枢神经系统更兴奋时，有助于回路发育的网络爆发是年轻海马体的一个标志。海马 CA3 神经元的自发活动很大程度上取决于后超极化电位 (AHP) 的内在电导。这种电导可以通过一类谷氨酸门控受体红藻氨酸受体（KAR）进行动态调节，这些受体与神经发育和神经精神疾病密切相关。新生儿 KAR 可能是发育中海马 AHP 的关键调节因子~然而，尚不清楚新生儿 KAR 的某些特性（例如它们的编辑状态、它们与特定信号通路的联系或它们如何被激活）是否使它们比成熟海马更有可能在新生儿海马中发挥这一作用。在这里，我们建议通过确定新生儿 KAR 如何产生 AHP 的长期抑制来调节海马神经元的兴奋性来解决这些基本问题。总体而言，这些研究将确定新生儿 KAR 在调节海马体活动中的作用，并将弥补我们对其在发育回路中的专门作用的认识空白。 在目标 1 中，我们将使用体外电生理记录来确定 KARs是否在调节CA3海马神经元的自发活动中发挥作用。将对 KAR 敲除小鼠和仅表达成熟形式受体的突变小鼠进行记录，以确定这些操作如何影响海马神经元的自发爆发。 KAR 在早期发育过程中主要存在于突触外，这就提出了它们如何被激活的问题。在目标 2 中，我们假设突触外 KAR 可以被环境谷氨酸激活，这种形式的强直信号传导对于它们在新生儿中的特殊功能至关重要。最后，在目标 3 中，我们将确定如何在新生儿中激活突触外海马 KAR。我们将测试两个具体假设（i）新生儿 KAR 被突触谷氨酸（例如通过溢出）激活或（ii）由非常规机制（例如神经胶质细胞传递）释放的谷氨酸激活。 这些研究将共同​​确定新生儿 KAR 调节发育中海马体兴奋性的机制。新生儿发育过程的改变最终可能导致一些与 KAR 相关的神经发育和神经精神疾病，如智力低下、自闭症、精神分裂症、双相情感障碍和癫痫。