Interictal epileptiform discharges affect memory in an Alzheimer’s Disease mouse model

Abstract

AbstractInterictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological disease, such as Alzheimer’s Disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multi-layer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples (SPW-Rs), altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implicates that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory.Significant StatementPrevalence of neurodegenerative diseases and the number of people with dementia is increasing steadily. Therefore, novel treatment strategies for learning and memory disorders are urgently necessary. IEDs, apart from being a surrogate for epileptic brain regions, have also been linked to cognitive decline. Here we report that IEDs in human epilepsy patients and AD mouse models have similar local field potential characteristics and associated firing patterns of pyramidal cells and interneurons. Mice with more IEDs displayed fewer hippocampal SPW-Rs, poorer replay of spatial trajectories, and decreased memory performance. IED suppression is an unexplored target to treat cognitive dysfunction in neurodegenerative diseases.