The role of neonatal kainate receptors in developing hippocampal circuits.

描述（由申请人提供）：新生儿自发性电活动对突触完善和神经发育的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，有助于神经回路发育的网络爆发是年轻海马体的一个标志。海马CA3神经元的自发活动在很大程度上依赖于构成后超极化电位（AHP）的内在电导。这种传导可以由一类谷氨酸门控受体，盐酸盐受体（KARs）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KARs可能是发育中的海马体AHP的关键调节因子，然而尚不清楚新生儿KARs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是如何被激活的）是否使它们在新生儿中比在成熟海马体中更有可能发挥这一作用。在这里，我们建议通过确定新生儿KARs如何产生长期抑制ahp来调节海马神经元的兴奋性来解决这些基本问题。总的来说，这些研究将确定新生儿KARs在调节海马体活动中的作用，并将解决我们对其在发育回路中的特殊作用的知识空白。在目的1中，我们将使用体外电生理记录来确定

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.