Waveform-based classification of dentate spikes

Abstract

Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimers disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing. Author summaryThe entorhinal cortex and the dentate gyrus are regions of the brains hippocampal formation that play a crucial role in learning and memory. Their synchronous activation generates fast and high-amplitude electrophysiological patterns in the dentate gyrus, called dentate spikes (DSs). However, the functional role of DSs is still poorly understood. A technical limitation for the study of DSs is that their classification into types 1 and 2 is only possible through laminar profiles obtained by multicontact linear probes. In the present work, we propose a method to classify the different types of DSs through their waveforms, thus expanding the investigation of their significance in mnemonic processes by making possible their study in single-site recordings.