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

May 12, 2023Neurobiology of disease

Changes in fast-acting inhibitory neurons and brain rhythms between memory and decision areas during natural sleep in Alzheimer's model mice

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Abstract

An increase in the power of medial prefrontal cortex spindles and a decrease in hippocampal sharp-wave ripples were observed during NREM sleep in 16-month-old Appmice.

Increased synchronisation of parvalbumin-expressing interneuron activity was noted during NREM sleep.
A decrease in the density of parvalbumin-expressing interneurons was identified in the studied mice.
No alterations in gamma oscillations were found in the hippocampus or medial prefrontal cortex during awake behaviour, REM, or NREM sleep.
Changes in local network function were observed in the medial prefrontal cortex and hippocampus during NREM sleep.
Long-range communication between the medial prefrontal cortex and hippocampus appeared to remain intact despite local impairments.

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In the early stages of Alzheimer's disease (AD), the accumulation of the peptide amyloid-β (Aβ) damages synapses and disrupts neuronal activity, leading to the 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 are 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 Appmouse model used in the present study. These mice appear to model the early stages of Aβ-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old Appmice, we analysed neuronal oscillations found in the hippocampus and 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 power of mPFC spindles and decrease in the power of hippocampal sharp-wave ripples was identified. The latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Caimaging, as well as a decrease in PV-expressing interneuron density. 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. NL-G-F/NL-G-F NL-G-F/NL-G-F2+

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

Abstract

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