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.
复制标题
一个计算网格到位置细胞的转换模型表明了早期阿尔茨海默病中位置细胞受损的一种突触驱动因素。
DOI：
10.1371/journal.pcbi.1009115
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发表时间：
2021-06
影响因子：
4.3
通讯作者：
Schultz SR
中科院分区：
文献类型：
--
作者：
Ness N;Schultz SR
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. Cognitive 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.
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. Cognitive 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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影响因子：
16.2
作者：
Brandon MP;Koenig J;Leutgeb JK;Leutgeb S
通讯作者：
Leutgeb S
DOI：
10.1523/jneurosci.6044-08.2009
发表时间：
2009-06-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
de Almeida L;Idiart M;Lisman JE
通讯作者：
Lisman JE
影响因子：
2.7
作者：
Clark JK;Furgerson M;Crystal JD;Fechheimer M;Furukawa R;Wagner JJ
通讯作者：
Wagner JJ
影响因子：
64.8
作者：
Attardo A;Fitzgerald JE;Schnitzer MJ
通讯作者：
Schnitzer MJ
DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur