title: APOE-Sensitive Cholinergic Sprouting Compensates for Hippocampal Dysfunctions Due to Reduced Entorhinal Input.
abstract: Brain mechanisms compensating for cerebral lesions may mitigate the progression of chronic neurodegenerative disorders such as Alzheimer's disease (AD). Mild cognitive impairment (MCI), which often precedes AD, is characterized by neuronal loss in the entorhinal cortex (EC). This loss leads to a hippocampal disconnection syndrome that drives clinical progression. The concomitant sprouting of cholinergic terminals in the hippocampus has been proposed to compensate for reduced EC glutamatergic input. However, in absence of direct experimental evidence, the compensatory nature of the cholinergic sprouting and its putative mechanisms remain elusive. Transgenic mice expressing the human APOE4 allele, the main genetic risk factor for sporadic MCI/AD, display impaired cholinergic sprouting after EC lesion. Using these mice as a tool to manipulate cholinergic sprouting in a disease-relevant way, we showed that this sprouting was necessary and sufficient for the acute compensation of EC lesion-induced spatial memory deficit before a slower glutamatergic reinnervation took place. We also found that partial EC lesion generates abnormal hyperactivity in EC/dentate networks. Dentate hyperactivity was abolished by optogenetic stimulation of cholinergic fibers. Therefore, control of dentate hyperactivity by cholinergic sprouting may be involved in functional compensation after entorhinal lesion. Our results also suggest that dentate hyperactivity in MCI patients may be directly related to EC neuronal loss. Impaired sprouting during the MCI stage may contribute to the faster cognitive decline reported in APOE4 carriers. Beyond the amyloid contribution, the potential role of both cholinergic sprouting and dentate hyperactivity in AD symptomatogenesis should be considered in designing new therapeutic approaches.
  
  
  
  Currently, curative treatment trials for Alzheimer's disease (AD) have failed. The endogenous ability of the brain to cope with neuronal loss probably represents one of the most promising therapeutic targets, but the underlying mechanisms are still unclear. Here, we show that the mammalian brain is able to manage several deleterious consequences of the loss of entorhinal neurons on hippocampal activity and cognitive performance 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 AD, especially in APOE4 carriers.
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7364, Neuropôle de Strasbourg Groupement De Recherche Européen/Centre National de la Recherche Scientifique 2905, F-67000 Strasbourg, France; and Université de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Jean-Bastien
authors.identifier: 0000-0003-3954-2467
authors.initials: JB
authors.lastname: Bott
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7364, Neuropôle de Strasbourg Groupement De Recherche Européen/Centre National de la Recherche Scientifique 2905, F-67000 Strasbourg, France; and Université de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Céline
authors.identifier: 0000-0002-9208-2335
authors.initials: C
authors.lastname: Héraud
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7364, Neuropôle de Strasbourg Groupement De Recherche Européen/Centre National de la Recherche Scientifique 2905, F-67000 Strasbourg, France; and Université de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Cosquer
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7364, Neuropôle de Strasbourg Groupement De Recherche Européen/Centre National de la Recherche Scientifique 2905, F-67000 Strasbourg, France; and Université de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Herbeaux
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7364, Neuropôle de Strasbourg Groupement De Recherche Européen/Centre National de la Recherche Scientifique 2905, F-67000 Strasbourg, France; and Université de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Aubert
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7364, Neuropôle de Strasbourg Groupement De Recherche Européen/Centre National de la Recherche Scientifique 2905, F-67000 Strasbourg, France; and Université de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Maxime
authors.identifier: 0000-0002-1192-1636
authors.initials: M
authors.lastname: Sartori
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7364, Neuropôle de Strasbourg Groupement De Recherche Européen/Centre National de la Recherche Scientifique 2905, F-67000 Strasbourg, France; and Université de Strasbourg, F-67000 Strasbourg, France.
authors.forename: Romain
authors.identifier: 0000-0002-1268-533X
authors.initials: R
authors.lastname: Goutagny
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7364, Neuropôle de Strasbourg Groupement De Recherche Européen/Centre National de la Recherche Scientifique 2905, F-67000 Strasbourg, France; and Université de Strasbourg, F-67000 Strasbourg, France chantal.mathis@unistra.fr.
authors.forename: Chantal
authors.identifier: 0000-0002-6663-5282
authors.initials: C
authors.lastname: Mathis
mesh_terms: D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000235:genetics; D002799:Cholinergic Fibers; D060825:Cognitive Dysfunction / Q000473:pathology / Q000503:physiopathology; D018891:Dentate Gyrus / Q000098:blood supply / Q000473:pathology; D018728:Entorhinal Cortex / Q000098:blood supply / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000098:blood supply / Q000473:pathology*; D006801:Humans; D008297:Male; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D062308:Optogenetics; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000503:physiopathology*; D065852:Spatial Memory; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4; C493465:Slc17a7 protein, mouse; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D050598:Vesicular Glutamate Transport Protein 1
keywords: APOE4; Alzheimer's disease; cholinergic sprouting; entorhinal cortex; hippocampal disconnection; spatial memory