Amyloid-β acute exposition affects the CA1 hippocampal network activity and its topological organization, evaluated with Multielectrode Arrays

David Alcantara-Gonzalez^1*Elizabeth Santiago²Fernando Peña-Ortega^3*

• ¹The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, United States
• ²Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
• ³Universidad Nacional Autonoma de Mexico Instituto de Neurobiologia, Juriquilla, Mexico

Abstract. Introduction. Neuronal networks enable brain's information processing through a well-coordinated activity. Disruptions in this activity can impair key brain functions such as synaptic plasticity and long-term memory. Such dysfunctions are relevant to the cognitive deterioration in Alzheimer's disease (AD). Neuronal circuit alterations in AD are associated with amyloid-β (Aβ) extracellular accumulation across multiple brain regions involved in cognitive regulation. Although several studies have analyzed network topology and examined anatomical, functional, and effective connectivity to understand their role in AD, the direct contribution of Aβ to local neuronal network disturbances has not been investigated. Methods. We assessed the CA1 hippocampal network structure after acute exposure to Aβ1-42 (30 nM) using an in vitro multielectrode array approach. We analyzed neuronal spiking activity recordings, evaluated the frequency of spontaneous synchronized events, and assessed functional connectivity to elucidate the functional alterations in the network. We also elucidated the statistical features of network topology using Graph Theoretical analysis, small-world network properties, and network classification using the Estrada index approach. Results. CA1 hippocampal neurons showed an average reduced firing frequency. However, some putative pyramidal neurons and interneurons increased their activity. These differences in activity are cell-type-specific, being the interneurons the cells that mainly reduce their firing in presence of Aβ. The number and magnitude of their functional links within the network were not different, but a synchronized firing pattern of different neurons was observed. These changes were associated with alterations to the network's topological structure, indicating the generation of highly connected nodes in the presence of Aβ. Conclusions. The main change in the reconfiguration of the CA1 hippocampal network induced by acute exposure to Aβ involved the differential change in firing of different neurons, where the average reduction in firing was found, but some neurons increased their firing. This may constitute an adaptive mechanisms that compensate for neuronal connectivity and help maintain the level of activity. This is the first time the Estrada index has been used to elucidate alterations in the topological neuronal network in an ex vivo brain preparation, highlighting its greater sensitivity for detecting changes compared to other topological network analysis approaches.