Glycine receptor synaptic plasticity

描述（由申请人提供）：尽管甘氨酸受体在与人类健康相关的神经系统关键区域具有重要意义，但对甘氨酸突触强度的调节知之甚少，对功能回路中的甘氨酸突触的了解更少。甘氨酸能突触包括脊髓、脑干和中脑的抑制驱动控制网络，调节运动行为、节奏产生、体感、听觉和视网膜信号，以及反射反应的协调。我们的长期目标是了解如何控制中枢神经系统甘氨酸能突触的强度，为脊髓和脑干回路疾病提供新的药物靶点。本研究计划的目的是通过对青春期小鼠完整脊髓切片的功能研究，确定甘氨酸能突触的增强是如何被触发和维持的。通过脊髓切片的电生理记录，我们发现炎症细胞因子il -1 β可以快速上调背角抑制性神经元上的抑制性甘氨酸受体。据我们所知，这是中枢神经系统中甘氨酸受体长期增强（LTP）的第一个例子。对抑制性背角神经元的快速抑制有望促进疼痛信号向大脑的传递，可能有助于鞘内il -1 β的已知伤害性作用。我们的初步数据支持本应用中需要验证的假设：外周损伤在背角释放的il -1 β激活细胞粘附分子和细胞内蛋白激酶级联反应，迅速增加突触甘氨酸能受体的数量。该研究的基本原理是，通过识别通常控制甘氨酸突触强度的信号级联，我们将为治疗疼痛和其他甘氨酸受体依赖性疾病提供新的治疗靶点。拟议的实验将阐明参与甘氨酸能LTP的信号通路和受体亚型（目的1和2），主要依赖于脊髓切片的敏感电生理记录。我们的初步结果还表明，体内炎症增强甘氨酸能突触，类似于在体外观察到的il -1 β增强。因此，我们将确定甘氨酸受体LTP在外周炎症后的作用

DESCRIPTION (provided by applicant): Despite the great importance of glycine receptors in key areas of the nervous system with relevance for human health, remarkably little is known about the regulation of glycinergic synapse strength, and even less about glycinergic synapses in functional circuits. Glycinergic synapses comprise much of the inhibitory drive controlling networks in the spinal cord, brainstem and midbrain, regulating motor behavior, rhythm generation, somatosensory, auditory, and retinal signaling, and coordination of reflex responses. Our long-term goal is to understand how to control the strength of glycinergic synapses in the central nervous system to provide novel drug targets for disorders of spinal cord and brainstem circuits. The objective of this research proposal is to define how potentiation of glycinergic synapses is triggered and maintained, using functional studies in intact spinal cord slices from adolescent mice. Using electrophysiological recordings in spinal cord slices, we find that the inflammatory cytokine, IL-1beta, rapidly upregulates inhibitory glycine receptors on inhibitory neurons in the dorsal horn. To our knowledge, this is the first example of long-term potentiation (LTP) of glycine receptors anywhere in the CNS. The rapid inhibition of inhibitory dorsal horn neurons is expected to promote the transmission of pain signals to the brain, likely contributing to the known nociceptive effects of intrathecal IL-1beta. Our preliminary data support the hypothesis to be tested in this application: that IL-1beta released in the dorsal horn by peripheral injury activates cell adhesion molecules and intracellular protein kinase cascades, rapidly increasing synaptic glycinergic receptor numbers. The rationale for the proposed research is that by identifying the signaling cascades that normally control glycinergic synapse strength, we will provide novel therapeutic targets to treat pain and other glycine receptor-dependent disorders. Proposed experiments will elucidate the signaling pathways and receptor subtypes involved in glycinergic LTP (Aims 1 and 2), primarily relying on sensitive electrophysiological recordings in spinal cord slices. Our preliminary results also indicate that inflammation in vivo potentiates glycinergic synapses, similarly to IL-1beta potentiation observed in vitro. We will therefore identify the role of glycine receptor LTP after peripheral inflammation (Aim 3), using electrophysiological and behavioral assays. The proposed work is innovative, in our opinion, because 1) we have identified the first example of LTP at glycinergic synapses in the mammalian CNS, and 2) as synaptic plasticity can underlie pathology, delineating the underlying mechanisms offers a new way to control glycinergic synapses in disease. The contributions of this research will be the elucidation of as yet entirely unknown mechanisms underlying glycine receptor signaling and synaptic potentiation in a developed tissue setting. These contributions are significant because they constitute critical first steps towards the development of new treatments for pain, respiratory and motor disorders, and auditory disorders.