Hippocampal sub-networks exhibit distinct spatial representation deficits in Alzheimer’s disease model mice

Rechnitz, Ohad; Slutsky, Inna; Morris, Genela; Derdikman, Dori

doi:10.1016/j.cub.2021.05.039

Cited by 10 publications

(7 citation statements)

References 83 publications

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“…The predominant effect on temporal firing rather than on spatial properties of CA1 cells differs from previous studies in pan-neuronal models of amyloidosis that have linked impaired spatial properties of spatially modulated cells, such as place 6,11,29 and grid cells 7,13 with memory deficits. However, the majority of previous recordings were performed at advanced stages of amyloid pathology, when plaques, robust spine loss and sometimes cell death were already present.…”

Section: Discussioncontrasting

confidence: 93%

Localized APP pathology in the hippocampus is sufficient to result in progressive disorganization of the timing of neuronal firing patterns

Silva

Haberl

Gaur

et al. 2022

Preprint

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Deficits in spatial navigation are among the early symptoms in Alzheimer's disease patients, consistent with the hippocampal formation as the site for spatial computations and disease onset. Although the correspondence between the early symptoms and brain regions that are affected early in the disease has been recognized, it is not clear whether progressive cognitive decline is solely caused by a spreading pathology or whether a focal pathology can by itself cause aberrant neuronal activity in a larger network. These possibilities cannot be distinguished in standard disease models which broadly express APP across brain regions. We therefore generated a mouse model in which the expression of mutant human APP was limited to hippocampal CA3 cells (CA3-APP mice). We first asked whether the limited pathology in CA3 can result in memory deficits and found impaired performance of CA3-APP mice in a hippocampus-dependent memory task. By then recording in the CA1 region, we asked to what extent neuronal activity patterns emerged in a brain region which received projections from APP-expressing CA3 cells, but did itself not show any primary pathology. While the spatial firing patterns of CA1 cells were preserved, we observed a reduced theta oscillation frequency in the local field potential and in a subpopulation of principal cells in CA1. Furthermore, CA1 interneurons showed decreased theta oscillation frequencies, and this effect was even more pronounced in CA3 interneurons, which also do not directly express APP. Pathology that is highly localized and limited to presynaptic cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from a spreading molecular pathology but also mediated by progressive physiological dysfunction.

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Section: Discussioncontrasting

confidence: 93%

Localized APP pathology in the hippocampus is sufficient to result in progressive disorganization of the timing of neuronal firing patterns

Silva

Haberl

Gaur

et al. 2022

Preprint

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“…At the single-unit level, APP-KI ( App NL−G-F ) mice displayed normal CA1 MFRs during active wakefulness, while exploring a familiar environment ( Jun et al., 2020 ). In addition, normal MFRs were detected in the CA3 and dentate gyrus of APP/PS1 mice during exploratory behavior ( Rechnitz et al., 2021 ). Even if some abnormal brain activity can be revealed under specific conditions in active wakefulness, our results strongly suggest a robust increase in excitability by general anesthetics as a common feature of different fAD models.…”

Section: Discussionmentioning

confidence: 99%

Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models

et al. 2022

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Summary Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer’s disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

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“…, 2005 ) with environmental enrichment—an important source of which in humans is regular social contact. Recently, invasive cell-recording experiments also showed that AD model mice have a selective impairment in pattern separation as subserved by the DG and CA3 ( Rechnitz et al. , 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Lacking social support is associated with structural divergences in hippocampus–default network co-variation patterns

Zajner

Spreng

Bzdok

2022

Social Cognitive and Affective Neuroscience

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Elaborate social interaction is a pivotal asset of the human species. The complexity of people’s social lives may constitute the dominating factor in the vibrancy of many individuals’ environment. The neural substrates linked to social cognition thus appear especially susceptible when people endure periods of social isolation: here, we zoom in on the systematic inter-relationships between two such neural substrates, the allocortical hippocampus (HC) and the neocortical default network (DN). Previous human social neuroscience studies have focused on the DN, while HC subfields have been studied in most detail in rodents and monkeys. To bring into contact these two separate research streams, we directly quantified how DN subregions are coherently co-expressed with specific HC subfields in the context of social isolation. A two-pronged decomposition of structural brain scans from ~40,000 UK Biobank participants linked lack of social support to mostly lateral subregions in the DN patterns. This lateral DN association co-occurred with HC patterns that implicated especially subiculum, presubiculum, CA2, CA3, and dentate gyrus. Overall, the subregion divergences within spatially overlapping signatures of HC-DN co-variation followed a clear segregation divide into the left and right brain hemispheres. Separable regimes of structural HC-DN co-variation also showed distinct associations with the genetic predisposition for lacking social support at the population level.

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Hippocampal sub-networks exhibit distinct spatial representation deficits in Alzheimer’s disease model mice

Cited by 10 publications

References 83 publications

Localized APP pathology in the hippocampus is sufficient to result in progressive disorganization of the timing of neuronal firing patterns

Localized APP pathology in the hippocampus is sufficient to result in progressive disorganization of the timing of neuronal firing patterns

Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models

Lacking social support is associated with structural divergences in hippocampus–default network co-variation patterns

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