Mechanisms underlying an impairment of visual response properties in mouse models of Alzheimer’s disease

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dc.contributor.advisor Garaschuk, Olga (Prof. Dr.) Asavapanumas, Nithi 2019-05-03T07:57:29Z 2019-05-03T07:57:29Z 2021-04-29
dc.identifier.uri de_DE
dc.description.abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which affects around 50 million people worldwide. Besides impairment of memory and cognition, which are common in AD, it is accompanied by an impairment of visual processing. Up to now there is no curative therapy for AD. The available drugs provide only symptomatic treatment, which has no effect on the causes of the disease. Therefore, a better understanding of the underlying causes and the identification of new therapeutic targets are required. Recently, neuronal hyperactivity has been widely recognized as one of the key functional impairments in AD as well as in the normal ageing. Previous study suggested the relationship between neuronal hyperactivity and the visual impairments in the mouse model of AD. However, the underlying mechanisms remain unclear. Using in vivo two photon Ca2+ imaging, the effect of ageing, an obvious risk factor of AD, on the ongoing neuronal activity in the primary visual cortex (V1) of 3, 10-12 and 18 months old mice were first characterized in this study. Ageing-related neuronal hyperactivity was found in 18 months old mice and was accompanied by an impairment of orientation tuning without changes in the direction tuning and visual responsiveness. Interestingly, the age-dependency of ageing-related neuronal hyperactivity in V1 is differs from that found in the frontal/motor cortex, suggesting a differential regional vulnerability to ageing. Subsequently, animal models of AD were used to study AD-related changes in neuronal properties in V1. We found neuronal hyperactivity in V1 of APPSWE/PS1G384A and PS1G384A mice, which lack amyloid plaque deposition and neuroinflammation. AD- related neuronal hyperactivity in V1 was accompanied by an over-responsiveness to visual stimuli and impaired visual tuning properties (both direction and orientation selectivity) of individual neurons. These impairments were largely caused by an insufficient suppression of responses to non-preferred orientation/direction stimuli. Moreover, visual stimulation robustly suppressed the ongoing spontaneous activity in WT but not in APPSWE/PS1G384A mice. Finally, we tested the effect of reducing store-mediated neuronal hyperactivity on the impairment of visual processing in AD mice. Emptying intracellular Ca2+ stores significantly reduced neuronal hyperactivity and the pathological over-responsiveness to visual stimuli but could not rescue stimulus-induced suppression of spontaneous activity and impaired tuning properties of individual cells. Thus, our data identify the AD- mediated dysfunction of intracellular Ca2+ stores as a main cause of pathologically increased visual responsiveness in APPSWE/PS1G384A mice. However, the impairment of visual tuning and the stimulus-induced suppression of spontaneous activity, identified in this study, are likely caused by different mechanisms, for example, dysfunction of local interneurons. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podno de_DE
dc.rights.uri de_DE
dc.rights.uri en
dc.subject.classification Alzheimerkrankheit , In vivo , Calcium de_DE
dc.subject.ddc 500 de_DE
dc.subject.other Alzheimer en
dc.subject.other Visual processing en
dc.subject.other neuronal hyperactivity en
dc.title Mechanisms underlying an impairment of visual response properties in mouse models of Alzheimer’s disease en
dc.type Dissertation de_DE
dcterms.dateAccepted 2019-04-26
utue.publikation.fachbereich Biologie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.source erschienen in: Neurobiol Dis. 2018 Oct 24; 121:315-326. doi: 10.1016/j.nbd.2018.10.015 und Proc Natl Acad Sci U S A. 2018 Feb 6; 115(6): E1279-E1288. doi: 10.1073/pnas. de_DE
utue.publikation.noppn yes de_DE


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