Network-level restoration of impaired memory function in early Alzheimer's disease via GluN2B modulation: insights from a hippocampal CA1-CA3 model.

Memory storage and recall are essential tasks for the healthy function of the hippocampus, adversely affected by neurodegenerative diseases, such as Alzheimer's Disease (AD). Pathological levels of amyloid-β peptide (Aβ), found already in early-stage AD, can disrupt the NMDAR-dependent plasticity at hippocampal networks. Here we investigate these effects in a biophysically detailed computational model of a hippocampal CA1-CA3 network and examine potential mechanisms of functional recovery. We show that, at a network level, long-term potentiation (LTP) impairments caused by Aβ accumulation can be substantially restored by partially blocking the GluN2B-NMDA receptors-a mechanism previously observed and modeled only at a single cell level. Experimental access to network-level processes of memory storage and recall in pathological conditions remains highly challenging. Therefore, computational modeling may help to bridge the gap between cellular impairments and system-level cognitive dysfunction. Our work transfers the established GluN2B-dependent rescue mechanisms from single cells to a network-level system of hippocampal pyramidal neurons and interneurons. The results demonstrate that also at a higher cognition level, the partial inhibition of the activity of GluN2B-NMDA receptors can be an effective strategy to counteract early AD impairments on memory storage and recall.