Reduced Inhibition Leads to Neuronal Hyperexcitability and Increased Spatial Imprecison of Place Cell Activity in APP/PS1 Mice Showing Impaired Spatial Learning

Falko Fuhrmann1, Pavol Bauer2, Dennis Dalügge2, Carolin Miklitz1, Stefan Remy2

1 German Centre for Neurodegenerative Diseases (DZNE)
2 German Centre for Neurodegenerative Diseases (DZNE) and Leibniz Institute for Neurobiology (LIN)

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Alzheimer's disease (AD) is one of the remaining primary dementias in which the cognitive decline is directly linked to brain changes. Earliest signs of AD pathology are found in entorhinal-hippocampal regions. These brain regions are crucial for the processing of spatial and temporal information as well as for the formation and retrieval of memories. In this work we focus on pathophysiological changes in the hippocampal formation, that impact learning ability, memory and cognitive performance. New insights in AD pathology research uncover dysfunction in local neuronal circuits as well as large-scale networks due to an imbalance of synaptic excitation and inhibition (E/I balance).Yet it is not fully understood how these alterations affect hippocampal network activity and learning ability in awake behaving animals.

In this study, we systematically performed 2-photon Ca2+ imaging of hippocampal population activity of 12 month old APPSwe/PS1dE9 mice (APP/PS1 mice) during a spatial reward learning task. Brain slice patch clamp recordings and voltage-sensitive dye imaging experiments revealed reduced inhibitory synaptic connectivity in the hippocampal CA1 area of APP/PS1 mice.

In the calcium imaging data, consistent with decreased inhibition as a potential mechanism, we detected increased activity of hippocampal place- and non-place-cells and increased out of place-field activity of place-cells in APP/PS1 mice. Moreover, we observed an altered reward seeking strategy of APP/PS1 mice, consistent with disturbed spatial orientation. Taken together this study identifies impaired inhibition as the underlying pathomechanism affecting the hippocampal network, population activity and animal behavior in APP/PS1 mice at plaque stages.