Linking Synaptic Properties to Neural Network Operation

描述（由申请人提供）：本提案的目标是了解神经网络活动与连接单个神经元的突触属性之间的相互作用。 拟议研究的理由是基于上一个赠款周期的若干发现。 在去抑制海马切片制备的CA3区，当有足够强度的连接该区域锥体细胞的复发性侧支突触时，网络活动的爆发是可能的。 因此，这些突触强度的短期活动依赖性抑制终止了爆发，而从这种短期抑制中恢复决定了下一次爆发的可能性。 此外，这些突触强度的长期决定因素也会影响爆发概率，因此长时程增强（LTP）和长时程抑制（LTD）都会在爆发时间上产生相应的长期变化。 在适当的条件下，爆发活动可以诱导LTP或LTD。 在LTD的情况下，强度的变化通过进一步LTP或LTD诱导的阈值的相关变化而稳定。 在下一个周期中，我们将测试与这些发现相关的两个假设。 首先，CA3中的短期突触抑制的一个组成部分似乎是由树突状钙内流介导的。我们将检验腺苷作用于突触前A1受体介导这种不寻常的短期抑郁机制的假设。第二，我们将调查的机制，长期突触可塑性的阈值改变CA3。 我们将测试的假设，减少最大的NMDA受体介导的突触后钙离子内流与LTD。最后，我们将测试这些突触特性和网络行为之间的关系可能会影响癫痫发作和治疗癫痫发作。 这些研究将帮助我们了解是什么决定了发作间期癫痫活动的时间，这是为了使用发作间期活动的时间模式来预测未来癫痫发作的概率所必需的。此外，这些研究将帮助我们了解如何通过在癫痫灶中最活跃的突触处选择性诱导LTD来产生稳定的、长期的癫痫发作概率降低。

DESCRIPTION (provided by applicant): The goal of this proposal is to understand the interactions between the activity of a neural network and the properties of the synapses that link the individual neurons. The rationale for the proposed studies is based on several discoveries made during the last grant cycle. In area CA3 of the disinhibited hippocampal slice preparation, bursts of network activity are possible when there is sufficient strength of the recurrent collateral synapses that link the pyramidal cell in this area. Thus short-term, activity-dependent depression of the strength of these synapases terminates bursts, and recovery from this short-term depression determines when the next burst is possible. Further, long-term determinants of the strength of these synapses also affect burst probability, so that both long-term potentiation (LTP) and long-term depression (LTD) produce corresponding long-term changes in burst timing. Under the appropriate conditions, burst activity can induce either LTP or LTD. In the case of LTD, the changes in strength are stabilized by an associated change in the threshold for further LTP or LTD induction. In the next cycle we propose to test two hypotheses related to these findings. First, one component of short-term synaptic depression in CA3 appears to be mediated by dendritic calcium influx. We will test the hypothesis that adenosine acting at presynaptic A1 receptors mediates this unusual mechanism of short-term depression. Second, we will investigate the mechanism by which the threshold for long-term synaptic plasticity is altered in CA3. We will test the hypothesis that a reduction in the maximum NMDA receptor-mediated postsynaptic calcium influx is associated with LTD. Finally, we will test how these relationships between synaptic properties and network behavior may affect epileptogenesis and the treatment of seizures. These investigations will help us understand what determines the timing of interictal epileptic activity, which is needed in order to use the temporal pattern of interictal activity to predict the probability of future seizures. In addition, these investigations will help us understand how to produce stable, long-term decreases in the probability of seizures by selective induction of LTD at the most active synapses in epileptic foci.