The role of neonatal kainate receptors in developing hippocampal circuits.

描述(申请人提供)：新生儿的自发电活动对神经发育的突触完善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容易兴奋时，有助于电路发展的网络爆发是年轻海马体的一个标志。海马区CA3神经元的自发活动在很大程度上依赖于支撑后超极化电位(AHP)的内在电导。这种电导可以被一类谷氨酸门控受体--海人酸受体(KARS)动态调节，KARS与神经发育和神经精神障碍密切相关。新生KAR可能是发育中的海马区AHP的关键调节因子~然而，尚不清楚新生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，或者它们是如何被激活的)，是否使它们更有可能在新生海马体中发挥这一作用，而不是成熟的海马体。在这里，我们建议通过确定新生KARs如何产生对AHPs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KARs在调节海马体活动中的作用，并将解决我们对它们在发育回路中的专门作用的认识上的空白。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区神经元自发活动中起作用。将从KAR基因敲除小鼠和只表达成熟受体的突变小鼠中进行录音，以确定这些操作如何影响海马神经元的自发爆发。KAR在早期发育中主要是突触外的，这引发了他们可能如何被激活的问题。在目标2中，我们假设突触外KARs可以被环境中的谷氨酸激活，这种形式的紧张性信号对它们在新生儿中的特殊功能至关重要。最后，在目标3中，我们将确定突触外的海马KARS如何在新生儿中被激活。我们将检验两个特定的假设(I)新生儿KAR被突触谷氨酸激活(例如通过溢出)或(Ii)由非常规机制释放的谷氨酸激活(例如神经胶质传递)。这些研究将共同确定新生儿KARs调节发育中海马区兴奋性的机制。新生儿发育过程的改变最终可能导致与KARS相关的一些神经发育和神经精神障碍，如智力低下、自闭症、精神分裂症、双相情感障碍和癫痫。

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.