Summary Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer’s disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

Summary Spontaneous spiking activity depends on intrinsic excitability and synaptic input. Historically, synaptic activity has been mostly studied ex vivo . Here, we describe a versatile and robust protocol to record field excitatory postsynaptic potentials (fEPSPs) in behaving rodents. The protocol allows estimating the input–output relationship of a specific pathway, short-term and long-term plasticity, and their modulation by pharmacological or pharmacogenetic interventions and behavioral states. However, experimenters must be aware of the protocol’s specificity and interpret results with care. For complete details on the use and execution of this profile, please refer to Styr et al. (2019) .