Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease

•Recorded locus coeruleus (LC) neurons in a rat model of Alzheimer's disease (AD).•TgF344-AD rats develop early endogenous LC tau pathology akin to human AD.•Six and 15 month TgF344-AD rats had reduced tonic LC firing.•LC neurons from 6-month TgF344-AD rats were hyperactive in response to footshock.•LC neuron dysfunction may contribute to AD symptoms. Hyperphosphorylated tau in the locus coeruleus (LC) is ubiquitous in prodromal Alzheimer's disease (AD), and LC neurons degenerate as AD progresses. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons are unknown. We assessed single unit LC activity in anesthetized wild-type (WT) and TgF344-AD rats at 6 months, which represents a prodromal stage when LC neurons are the only cells containing hyperphosphorylated tau in TgF344-AD animals, and at 15 months when amyloid-β (Aβ) and tau pathology are both abundant in the forebrain. At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates but showed elevated spontaneous bursting properties. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and 15-month transgenic rats showing hypoactivity. Early LC hyperactivity is consistent with appearance of prodromal neuropsychiatric symptoms and is followed by LC hypoactivity which contributes to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.