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

Abstract

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.