Control of sensory function in mammalian spinal cord

描述（由申请人提供）：感觉神经传递是感觉刺激的中枢处理的基本第一步。它由突触前和突触后抑制机制控制。突触前抑制比突触后抑制更能抑制几乎所有初级传入感觉纤维的中枢兴奋性活动。产生传入PSI的一个主要机制是通过一个违反直觉的通道介导的去极化，其椎管内的终端，方便地，可以记录为背根电位。据认为，通过三突触通路，GABA能抑制性中间神经元释放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，直到今天，几乎没有“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是由更直接的突触通路产生的，可能是：（i）独立于经典的GABAA受体和（ii）独立于GABA。这些断言的机制证据需要在体外神经连接的小鼠脊髓（P10-14）中的开拓性电生理学研究的结合，并且包括鉴定和敲除较大直径感觉传入亚群中的特定基因的转基因系。具体来说，我们将测试以下两个假设：1。GABA并不是产生PSI的唯一递质。替代物包括乙酰胆碱、牛磺酸和2-丙氨酸，这些在离散的传入和神经元间亚群中发现。 2. GABAA受体亚单位不是活化受体中唯一的亚单位。替代物是烟碱和甘氨酸能亚基，这些亚基可以组装成独特的异聚体组合物。如果成功的话，几十年来关于产生防扩散安全倡议的机制的观点将需要进行重大的概念修订。这种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。

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.