Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer’s Disease

Abstract Network hyperexcitability is a feature of Alzheimer’ disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APPNL/F). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APPNL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD

Functional impact of cholinergic dysfunction on retrosplenial circuits in the 5xFAD mouse model of Alzheimer- s disease

BackgroundThe retrosplenial cortex (RSC) is critical for learning, memory and spatial navigation and is one of the first brain regions to show dysfunctional activity in the earliest stages of Alzheimer- s disease. RSC receives dense cholinergic inputs from multiple basal forebrain regions. While decreased cholinergic tone is one of the hallmarks of the Alzheimer- s disease, it is not known how this change impacts retrosplenial cells and circuits. In wild- type mice, cholinergic agonists induce persistent firing in limbic areas such as the entorhinal cortex and the prefrontal cortex. This persistent firing has been proposed as an important neuronal substrate for working memory and successful spatial navigation.MethodHere, we investigated cholinergic- induced persistent firing in the retrosplenial cortex in the 5xFAD model of Alzheimer- s disease. We combined pharmacological and whole- cell patch clamp techniques to characterize the response of retrosplenial cortex cells to carbachol (20 uM), a non- specific cholinergic agonist, in both wild type and 5xFAD mice aged P30- P75.ResultIn wild type animals, persistent firing in response to carbachol in deep layers of the retrosplenial cortex was commonly observed (66.6% of all cells tested). This persistent firing was blocked by atropine (10uM) indicating that it is dependent on muscarinic cholinergic receptors. Retrosplenial cells in 5xFAD animals rarely showed persistent firing (20%, p<0.05, binomial test comparing wild type vs 5xFAD).ConclusionCholinergic hypofunction resulting from damage to basal forebrain neurons early in Alzheimer- s disease has widely been linked to cognitive impairment. Our results point to a complementary mechanism impacting cholinergic control of cortical circuits: muscarinic receptor downregulation in the earliest stages of Alzheimer- s disease. These changes prevent retrosplenial cortex cells of 5xFAD mice from responding to cholinergic activation with the kind of persistent firing that is important for working memory and spatial navigation, suggesting a mechanistic explanation for how cholinergic dysfunction leads to impaired spatial encoding by retrosplenial circuits.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163934/1/alz047611.pd