Alterations in hippocampal network oscillations and theta–gamma coupling arise before <scp>Aβ</scp> overproduction in a mouse model of <scp>A</scp>lzheimer's disease

<jats:title>Abstract</jats:title><jats:p>Alzheimer's disease (<jats:styled-content style="fixed-case">AD</jats:styled-content>) is an age‐related neurodegenerative disorder characterized by memory impairments. Brain oscillatory activity is critical for cognitive function and is altered in <jats:styled-content style="fixed-case">AD</jats:styled-content> patients. Recent evidence suggests that accumulation of soluble amyloid‐beta (<jats:styled-content style="fixed-case">A</jats:styled-content>β) induces reorganization of hippocampal networks. However, whether fine changes in network activity might be present at very early stages, before <jats:styled-content style="fixed-case">A</jats:styled-content>β overproduction, remains to be determined. We therefore assessed whether theta and gamma oscillations and their cross‐frequency coupling, which are known to be essential for normal memory function, were precociously altered in the hippocampus. Electrophysiological field potential recordings were performed using complete hippocampal preparations <jats:italic>in vitro</jats:italic> from young transgenic <jats:styled-content style="fixed-case">CRND</jats:styled-content>8 mice, a transgenic mouse model of <jats:styled-content style="fixed-case">AD</jats:styled-content>. Our results indicate that a significant proportion of 1‐month‐old <jats:styled-content style="fixed-case">T</jats:styled-content>g<jats:styled-content style="fixed-case">CRND</jats:styled-content>8 mice showed robust alterations of theta–gamma cross‐frequency coupling in the principal output region of the hippocampus, the subiculum. In addition we showed that, compared to controls, these mice expressed negligible levels of <jats:styled-content style="fixed-case">A</jats:styled-content>β. Finally, these network alterations were not due to genetic factors as 15‐day‐old animals did not exhibit theta–gamma coupling alterations. Thus, initial alterations in hippocampal network activity arise before <jats:styled-content style="fixed-case">A</jats:styled-content>β accumulation and may represent an early biomarker for <jats:styled-content style="fixed-case">AD</jats:styled-content>.</jats:p>