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bioRxiv · 10.1101/2022.02.08.479119

Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in APPNL-G-F mice

Brady, E. S.·Griffiths, J.·Andrianova, L.·Saito, T.·Sado, T. C.·Randall, A. D.·Tamagnini, F.·Witton, J.·Craig, M.
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Abstract

In the early stages of Alzheimers disease (AD), the accumulation of the peptide amyloid-{beta} (A{beta}) damages synapses and disrupts neuronal activity and leads to disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-F mouse model used in the present study. These mice appear to model the early stages of A{beta}-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-F mice, we analysed neuronal oscillations found in the hippocampal - medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the amplitude of mPFC spindles and decrease in the power of hippocampal SWRs was identified. The former was associated with a decrease in the density of mPFC PV-expressing interneurons and the latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+ imaging. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.

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Brady, E. S., Griffiths, J., Andrianova, L., Saito, T., Sado, T. C., Randall, A. D., Tamagnini, F., Witton, J., Craig, M.. 2022-02-10. Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in APPNL-G-F mice. https://doi.org/10.1101/2022.02.08.479119

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