Cellular Mechanisms Underlying the Long-term Potentiation of GABA Release

描述(申请人提供)：神经元活动可以改变突触传递的效果。这种突触强度的依赖于使用的变化可能会改变神经元电路中的信息处理和大脑中的信息存储，并被认为是学习和记忆的基础。这一领域的大部分努力都集中在兴奋性谷氨酸能突触的长期增强和抑制上。然而，关于抑制性突触传递是如何调控的，人们知之甚少。抑制性突触控制突触后神经元的时序和放电模式。因此，抑制性突触传递强度的持续变化可以改变突触后神经元的兴奋性，改变神经元回路中的信息处理。这种变化对大脑的生理功能和在癫痫等病理条件下发生的神经元兴奋性的变化都是必不可少的。例如，增强GABA传递可以控制许多患者的癫痫，而阻断GABA能神经传递会导致癫痫发作。我们最近的工作表明，小脑兴奋性突触输入的重复激活导致小脑中间神经元星状细胞分泌抑制性递质GABA的长期增加。这种变化需要激活星状细胞中的NMDA型谷氨酸受体，并增强突触后细胞对GABA的抑制性突触反应。我们建议研究GABA释放的活性依赖变化的潜在机制。在这项研究中，我们计划解决以下问题。首先，这种形式的可塑性在星状/篮状细胞到浦肯野细胞的突触以及在星状细胞之间的突触上也能被诱导吗？第二，哪些亚型的NMDA受体参与了小脑星状细胞GABA释放持续增加的诱导？第三，NMDA受体诱导的GABA释放增加的分子事件是什么？我们对抑制性传递活动依赖变化的细胞和分子机制的研究有助于我们理解运动学习的细胞机制以及与GABA能传递变化相关的神经障碍。

DESCRIPTION (provided by applicant): Neuronal activity can modify the efficacy of synaptic transmission. This use-dependent change in synaptic strength may alter information processing in neuronal circuitry and information storage in the brain, and is believed to underlie learning and memory. Much of the effort in this field focuses on the longer-term potentiation and depression at excitatory glutamatergic synapses. However little is known about how inhibitory synaptic transmission is regulated. Inhibitory synapses control the timing and firing patterns of the postsynaptic neuron. Thus a lasting alteration in the strength of inhibitory synaptic transmission can alter the excitability of the postsynaptic neuron changing information processing within a neuronal circuit. Such changes are essential for both the physiological functioning of the brain and for the alterations in neuronal excitability that occur under pathological conditions such as epilepsy. For example enhancing GABA transmission can control epilepsy in many patients, while blocking GABAergic neurotransmission generates seizures. Our recent work shows that repetitive activation of excitatory synaptic inputs in the cerebellum results in a long-lasting increase in the secretion of an inhibitory transmitter, GABA, from a cerebellar interneuron, the stellate cell. This change requires activation of NMDA-type glutamate receptors in stellate cells and enhances the inhibitory synaptic response to GABA in the postsynaptic cell. We propose to study the mechanisms underlying the activity-dependent change in GABA release. In this study, we plan to address the following questions. First, can this form of plasticity also be induced at the stellate/basket cell to Purkinje cell synapse and at the synapse between stellate cells? Second, which subtypes of NMDA receptors are involved in the induction of the lasting increase in GABA release from cerebellar stellate cells? Third, what are the molecular events that are responsible for NMDA receptor-induced enhancement of GABA release? Our investigation of cellular and molecular mechanisms underlying activity-dependent change in inhibitory transmission could contribute to our understanding of cellular mechanisms underlying motor learning and the neurological disorders that is associated with changes in GABAergic transmission.