Romain Goutagny’s home-page

Hippocampal theta rhythm is crucial for spatial memory and is thought to be generated by extrinsic inputs. In contrast, we found that CA1 theta rhythm can emerge from the coupling of multiple autonomous hippocampal theta oscillators.

Alzheimer’s disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Even though the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis which posits that increased production of soluble amyloid beta peptide (Aβ) induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Aβ-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatment were given too late in the course of AD, when neuronal damages were already too extensive. Using an animal model of AD, we showed that some of the early memory deficits are Aβ independent. Our results could partly explain the limited efficacy of Aβ-directed treatments and favor multi-therapy approaches for early symptomatic treatment for AD. 

Currently, curative treatment trials for Alzheimer Disease have failed. The endogenous ability of the brain to cope with neuronal loss probably represents one of the most promising therapeutic targets, but underlying mechanisms are still undetermined. Here we show that the mammalian brain is able to manage the deleterious consequences of the loss of entorhinal neurons on both hippocampal activity and cognitive performance, first through a fast cholinergic sprouting followed by a slower glutamatergic reinnervation. The cholinergic sprouting is gender-dependent and highly sensitive to the genetic risk factor APOE4. Our findings highlight the specific impact of early loss of entorhinal input on hippocampal hyperactivity and cognitive deficits characterizing early stages of Alzheimer’s disease, especially in APOE4 carriers.

Brain oscillatory activity is critical for cognitive function and is altered in AD patients. Recent evidence suggests that accumulation of soluble amyloid-beta (Aβ) induces reorganization of hippocampal networks. However, whether fine changes in network activity might be present at very early stages, before Aβ overproduction, remains to be determined. We were able to show that initial alterations in hippocampal network activity (theta-gamma coupling) arise before Aβ accumulation and may represent an early biomarker for AD.