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

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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.