An investigation of medial prefrontal cortex – hippocampal circuit function in a mouse model of familial Alzheimer’s disease

Abstract

The communication between the medial prefrontal cortex (mPFC) and hippocampus is crucial for spatial memory, decision making and the long-term consolidation of our memories during sleep. This communication is mediated via the temporal coupling of key neuronal oscillations. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder which affects the electrical activity of the brain, causing disrupted neuronal oscillations and a decline in episodic, spatial and working memory. In the preclinical stages of the disease, sleep disruptions are common and are accompanied by impairments to several of the oscillations responsible for long-term memory consolidation in the mPFC-hippocampal circuit. However, less is known about how the functional interactions of the different neuronal oscillations in this circuit are affected. Additionally, impairments to the oscillations involved in spatial memory and decision making in the mPFC-hippocampal circuit are known to occur in first-generation mouse models of amyloidopathy, yet have been scarcely studied in second-generation models. Therefore, using in vivo electrophysiology, the oscillatory activity of this circuit was studied during sleep and exploratory behaviour in the second-generation APPNL-G-F mouse model of amyloidopathy, to investigate potential dysfunctions.

The neuronal oscillations in the mPFC-hippocampal circuit were studied during natural sleep. In these experiments, impairments to local oscillations in the mPFC and CA1 region of the hippocampus were identified, yet long-range coordination of oscillations between brain regions was unaffected. Additionally, the oscillations recorded in CA1 during spatial memory showed local disruptions. Finally, impairments to the function of inhibitory neurons have been proposed to underlie changes to the oscillatory dynamics of neuronal circuit activity in AD. Therefore, immunohistochemical analysis of interneuron protein markers was performed to complement electrophysiological analyses of mPFC and CA1 circuit function. Collectively, these experiments further our understanding of how the mPFC-hippocampal circuit is affected in AD and provide a basis to study the underlying circuit disruptions.