Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

Korzhova, Viktoria; Marinković, Petar; Goltstein, Pieter M.; Herms, Jochen; Liebscher, Sabine

doi:10.1101/801902

“…Korzhova et al [94] recently identified a progressive increase in activity of intermediately active cells as the primary source of highly active neurons in the cortex of APP/PS1 mice, which was also observed in our model, supporting their hypothesis that network pathology may stem from stable aberrant activity of single cells.…”

Section: Discussionsupporting

confidence: 89%

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease

Ness

¹

,

Schultz

²

2020

Preprint

0

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Alzheimer’s Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution.Author SummaryCognitive decline in Alzheimer’s Disease (AD) correlates most strongly with dysfunction and loss of synapses in affected brain regions. While synaptic dysfunction is a well-established early symptom of AD, how impaired synaptic transmission may lead to progressive cognitive decline, remains subject to active research. In this study, we examine the effect of synapse loss on neuronal network function using a computational model of place cells in the hippocampal network. Place cells encode a cognitive map of an animal’s environment, enabling navigation and spatial memory. This provides a useful indicator of cognitive function, as place cell function is well characterized and abnormalities in place cell firing have been shown to underlie navigational deficits in rodents. We find that synapse loss in our network is sufficient to produce progressive impairments in place cell function, which resemble those observed in mouse models of the disease, supporting the hypothesis that synaptic dysfunction may underlie the cognitive impairment in AD. Furthermore, we observe that loss of excitatory and inhibitory synapses produce distinct spatial impairments. Future experiments investigating the relative contribution of different synaptic inputs may thus allow new insights into the neuronal network alterations in AD and potentially enable the identification of new therapeutic targets.

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“…Korzhova et al [92] recently identified a progressive increase in activity of intermediately active cells as the primary source of highly active neurons in the cortex of APP/PS1 mice, which was also observed in our model, supporting their hypothesis that network pathology may stem from stable aberrant activity of single cells.…”

Section: Excitatory and Inhibitory Synapse Loss May Distinctly Contribute To Network Dysregulationsupporting

confidence: 89%

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease

Ness

¹

,

Schultz

²

2021

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Alzheimer’s Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution.

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“…2 ), which is in line with previous reports. 15 , 20 To characterize neuronal function, we quantified neuronal activity levels during stationary/quiescent epochs as well in response to whisking ( Fig. 1D ).…”

Section: Resultsmentioning

confidence: 99%

Cortical circuit dysfunction in a mouse model of alpha-synucleinopathy in vivo

Blumenstock

¹

,

Sun

²

,

Klaus

³

et al. 2021

Brain Communications

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Considerable fluctuations in cognitive performance and eventual dementia are an important characteristic of alpha-synucleinopathies, such as Parkinson’s disease and Lewy Body dementia and are linked to cortical dysfunction. The presence of misfolded and aggregated alpha-synuclein in the cerebral cortex of patients has been suggested to play a crucial role in this process. However, the consequences of a-synuclein accumulation on the function of cortical networks at cellular resolution in vivo are largely unknown. Here, we induced robust a-synuclein pathology in the cerebral cortex using the striatal seeding model in wild-type mice. Nine months after a single intrastriatal injection of a-synuclein preformed fibrils, we observed profound alterations of the function of layer 2/3 cortical neurons in somatosensory cortex by in vivo two-photon calcium imaging in awake mice. We detected increased spontaneous activity levels, an enhanced response to whisking and increased synchrony. Stereological analyses revealed a reduction in glutamic acid decarboxylase 67-positive inhibitory neurons in the somatosensory cortex of mice injected with preformed fibrils. Importantly, these findings point to a disturbed excitation/inhibition balance as a relevant driver of circuit dysfunction, potentially underlying cognitive changes in alpha-synucleinopathies.

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Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

Cited by 6 publications

References 50 publications

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease

Cortical circuit dysfunction in a mouse model of alpha-synucleinopathy in vivo

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