Computational and experimental investigation of heterosynaptic plasticity and pattern separation in adult-born dentate granule cells

成体出生的颗粒细胞具有独特的电生理特征，在海马记忆形成和模式分离中起着特殊的作用。年轻的abGC在4周龄时开始出现一个关键期，此时它们表现出更强的兴奋性、增强的突触可塑性和减少的抑制性输入。此外，我们最近发现，从第5周开始，年轻的abGC表现出同质和异质突触的结构可塑性。然而，abGC的这些性质和它们对模式分离的贡献之间的相互作用还没有被充分了解，也从未在生物现实模拟中被建模。因此，我们将解决以下主要问题：年轻abGC的特征属性如何影响其输入-输出转换，从而影响单细胞水平的模式分离？主要目标是更好地了解生物物理和计算规则，这些规则推动年轻的abGC作为齿状回中有效的模式分离器。我们的具体问题是：在年轻的abgc中观察到的较低的突触密度和较高的兴奋性对其输入输出功能有什么功能后果？年轻abGC的特征如何影响其发射的稀疏性？年轻abGC中独特的离子通道表达如何调节它们的输入输出功能、突触可塑性和模式分离？与成熟abGC相比，年轻abGC在离子通道表达、抑制和NMDA受体亚单位表达方面的已知差异是否完全解释了年轻abGC同源突触可塑性增强？同型突触增强(LTP)和异型突触减弱(LTD)是如何影响年轻abGC的模式分离性能的？同突触LTP和异突触LTD在单个年轻abGC水平上是否平衡？在稀疏颗粒细胞激发和模式分离方面，内部和外部(突触)参数之间是否存在协同或退化(即部分冗余)？参数空间中可解释实验观察到的可变性的实际可变性范围是多少？为了回答这些问题，我们有以下目标。利用计算和电生理方法的结合，我们的目标是：(1)改进和扩展现有的成熟GC和年轻abGC的隔室模型；(2)建立年轻abGC同源突触可塑性增强的模型并分析其潜在机制；(3)建立年轻abGC的异突触可塑性模型；(4)研究年轻abGC独特的内在/外在属性的计算作用及其对稀疏激发和模式分离的异突触可塑性；(5)建立模式分离的简化细胞和电路模型；(6)通过实验验证计算模型并测试其预测。新的和大大改进的齿状GC模型将免费提供。

Adult-born granule cells (abGCs) possess unique electrophysiological features and play a special role in hippocampal memory formation and pattern separation. Young abGCs display a critical phase starting at 4 weeks of cell age when they exhibit increased excitability, enhanced synaptic plasticity, and decreased inhibitory input. Moreover, we have recently shown that from the 5th week on, young abGCs show homo- and heterosynaptic structural plasticity. However, the interplay between these properties of abGCs and their contribution to pattern separation is not sufficiently understood and has never been modeled in biologically realistic simulations. Therefore, we will address the following major questions: How do characteristic properties of young abGCs shape their input-output transformation and thereby affect pattern separation at the single cell level? The principal goal is to better understand the biophysical and computational rules, which drive the establishment of young abGCs as efficient pattern separators in the dentate gyrus. Our specific questions are: What are the functional consequences of observed lower synapse density combined with higher excitability in young abGCs for their input-output function? How do characteristic features of young abGCs affect the sparseness of their firing? How does unique ion channel expression in young abGCs modulate their input-output function, synaptic plasticity and pattern separation? Can the known differences in ion channel expression, inhibition and NMDA-receptor subunit expression in young abGCs fully explain enhanced homosynaptic plasticity in young abGCs as compared to mature abGCs? How does homosynaptic synaptic strengthening (LTP) and heterosynaptic weakening (LTD) in young abGCs affect their pattern separation performance? Are homosynaptic LTP and heterosynaptic LTD balanced at the level of individual young abGCs? Is there a synergy or degeneracy (i.e. partial redundancy) between intrinsic and extrinsic (synaptic) parameters with respect to sparse granule cell firing and pattern separation? What is a realistic range of variability in the parameter space, which would explain experimentally observed variability? To answer these questions, we have the following objectives. Using a combination of computational and electrophysiological methods we aim to: (1) improve and extend existing compartmental models of mature GCs and young abGCs; (2) develop models of enhanced homosynaptic plasticity in young abGCs and analyze its underlying mechanisms; (3) develop models of heterosynaptic plasticity in young abGCs; (4) study the computational role of unique intrinsic/extrinsic properties of young abGCs and their heterosynaptic plasticity for sparse firing and pattern separation; (5) develop reduced cellular and circuit models of pattern separation; (6) validate computational models experimentally and test their predictions. New and greatly improved models of dentate GCs will be freely available.