Control of sensory function in mammalian spinal cord

描述(申请人提供)：感觉神经传递是感官刺激中央处理的基本第一步。它受突触前和突触后抑制机制的控制。突触前抑制(PSI)比突触后抑制更能抑制几乎所有初级传入纤维的中枢兴奋作用。产生传入PSI的一个主要机制是通过脊髓内终末的反直觉通道介导的去极化，这可以方便地记录为背根电位。据认为，GABA能抑制中间神经元通过三突触通路释放GABA作为神经递质，产生大直径(低阈值)肌肉和皮肤感觉传入的PSI。然而，到目前为止，几乎没有“几乎干净”的证据。相反，我们有异端证据表明，这种传入刺激诱发的PSI大部分是由更直接的突触通路产生的，这些突触通路可能：(I)不依赖于经典的GABAA受体，(Ii)不依赖于GABA。这些断言的机械证明需要在体外神经连接的小鼠脊髓(P10-14)中结合开创性的电生理学研究，并包括在更大直径的感觉传入亚群中识别和敲除特定基因的转基因品系。具体地说，我们将检验以下两个假设：1.GABA不是唯一产生PSI的递质。替代的包括乙酰胆碱、牛磺酸和2-丙氨酸，这些存在于离散的传入和神经元间亚群中。2.GABAA受体亚基不是激活受体中唯一的亚基。替代物是烟酸和甘氨酸能亚基，这些亚基可以组装成独特的异构体成分。如果成功，几十年来关于PSI产生机制的观点将需要戏剧性的概念修改。这一新的视角拓宽了我们对躯体感觉信息处理的理解，并可能为感觉功能障碍引入新的控制策略。 公共卫生相关性：我们建议对哺乳动物初级传入神经突触前抑制的机制进行详细的表征。

DESCRIPTION (provided by applicant): Sensory neurotransmission is the fundamental first step in the central processing of sensory stimuli. It is controlled by pre- and post-synaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is more powerful than postsynaptic inhibition in depressing the central excitatory actions of almost all primary afferent sensory fibers. A major mechanism producing afferent PSI is via a counterintuitive channel-mediated depolarization of their intraspinal terminals which, conveniently, can be recorded as a dorsal root potential. It is thought that, via a trisynaptic pathway, GABAergic inhibitory interneurons release GABA as the neurotransmitter to produce PSI of large-diameter (low threshold) muscle and cutaneous sensory afferents. However to this day there is little 'squeaky clean' evidence. We have heretical evidence suggesting instead that much of this afferent stimulation-evoked PSI is generated by more direct synaptic pathways that may be; (i) independent of classical GABAA receptors and (ii) independent of GABA. A mechanistic proof of these assertions require a coalescence of pioneering electrophysiological studies in the in vitro nerves-attached mouse spinal cord (P10-14) and includes transgenic lines that identify and knockout specific genes in larger- diameter sensory afferent subpopulation. Specifically, we will test the following two hypotheses: 1. GABA is not the only transmitter producing PSI. Alternates include acetylcholine, taurine and 2-alanine, and these are found in discrete afferent and interneuronal subpopulations. 2. GABAA receptor subunits are not the only subunits in activated receptors. Alternates are nicotinic and glycinergic subunits and these may be assembled in unique heteromeric compositions. If successful, a decades-old view of mechanisms producing PSI will require dramatic conceptual revision. This new perspective broadens our understanding of somatosensory information processing, and may introduce novel control strategies for sensory dysfunction. PUBLIC HEALTH RELEVANCE: We propose to undertake a detailed characterization of the mechanisms responsible for presynaptic inhibition of primary afferents in the mammal.