Ablation of p75(NTR) signaling strengthens gamma–theta rhythm interaction and counteracts Aβ-induced degradation of neuronal dynamics in mouse hippocampus in vitro

Gamma and theta brain rhythms play important roles in cognition and their interaction can affect gamma oscillation features. Hippocampal theta oscillations depend on cholinergic and GABAergic input from the medial septum-diagonal band of Broca. These projecting neurons undergo degeneration during aging and maintain high levels of neurotrophin receptor p75 (p75(NTR)). p75(NTR) mediates both apoptosis and survival and its expression is increased in Alzheimer’s disease (AD) patients. Here, we investigate the importance of p75(NTR) for the cholinergic input to the hippocampus. Performing extracellular recordings in brain slices from p75(NTR) knockout mice (p75(−/−)) in presence of the muscarinic agonist carbachol, we find that gamma oscillation power and rhythmicity are increased compared to wild-type (WT) mice. Furthermore, gamma activity is more phase-locked to the underlying theta rhythm, which renders a stronger coupling of both rhythms. On the cellular level, we find that fast-spiking interneurons (FSNs) fire more synchronized to a preferred gamma phase in p75(−/−) mice. The excitatory input onto FSN is more rhythmic displaying a higher similarity with the concomitant gamma rhythm. Notably, the ablation of p75(NTR) counteracts the Aβ-induced degradation of gamma oscillations and its nesting within the underlying theta rhythm. Our results show that the lack of p75(NTR) signaling could promote stronger cholinergic modulation of the hippocampal gamma rhythm, suggesting an involvement of p75(NTR) in the downregulation of cognition-relevant hippocampal network dynamics in pathologies. Moreover, functional data provided here suggest p75(NTR) as a suitable target in the search for efficacious treatments to counteract the loss of cognitive function observed in amyloid-driven pathologies such as AD.