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Journal ArticleDOI

Functional Alterations in the Olfactory Neuronal Circuit Occur before Hippocampal Plasticity Deficits in the P301S Mouse Model of Tauopathy: Implications for Early Diagnosis and Translational Research in Alzheimer's Disease.

30 Jul 2020-International Journal of Molecular Sciences (Multidisciplinary Digital Publishing Institute)-Vol. 21, Iss: 15, pp 5431
TL;DR: The alterations in network oscillations at the OB level and impairments in the functioning of the SC-CA1 pyramidal synapses strongly suggest that the progression of tau pathology elicited a brain area, activity-dependent disturbance in functional synaptic transmission in Alzheimer’s disease.
Abstract: Alzheimer’s disease (AD) is characterized by neuronal loss and impaired synaptic transmission, ultimately leading to cognitive deficits. Early in the disease, the olfactory track seems most sensitive to tauopathy, while most plasticity studies focused on the hippocampal circuits. Functional network connectivity (FC) and long-term potentiation (LTP), considered as the plasticity substrate of learning and memory, were longitudinally assessed in mice of the P301S model of tauopathy following the course (time and location) of progressively neurodegenerative pathology (i.e., at 3, 6, and 9 months of age) and in their wild type (WT) littermates. Using in vivo local field potential (LFP) recordings, early (at three months) dampening in the gamma oscillatory activity and impairments in the phase-amplitude theta-gamma coupling (PAC) were found in the olfactory bulb (OB) circuit of P301S mice, which were maintained through the whole course of pathology development. In contrast, LFP oscillatory activity and PAC indices were normal in the entorhinal cortex, hippocampal CA1 and CA3 nuclei. Field excitatory postsynaptic potential (fEPSP) recordings from the Shaffer collateral (SC)-CA1 hippocampal stratum pyramidal revealed a significant altered synaptic LTP response to high-frequency stimulation (HFS): at three months of age, no significant difference between genotypes was found in basal synaptic activity, while signs of a deficit in short term plasticity were revealed by alterations in the fEPSPs. At six months of age, a slight deviance was found in basal synaptic activity and significant differences were observed in the LTP response. The alterations in network oscillations at the OB level and impairments in the functioning of the SC-CA1 pyramidal synapses strongly suggest that the progression of tau pathology elicited a brain area, activity-dependent disturbance in functional synaptic transmission. These findings point to early major alterations of neuronal activity in the OB circuit prior to the disturbance of hippocampal synaptic plasticity, possibly involving tauopathy in the anomalous FC. Further research should determine whether those early deficits in the OB network oscillations and FC are possible mechanisms that potentially promote the emergence of hippocampal synaptic impairments during the progression of tauopathy.
Citations
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Journal ArticleDOI
TL;DR: In this paper, the authors compare different aspects of the aging and Alzheimer's disease related impairment of olfaction in men and mice, aiming at the identification of common morbidities and biomarkers, which can be analyzed in detail in the appropriate mouse models.
Abstract: Olfaction, or the sense of smell, is one of the most ancient senses in men and mice, important for a large variety of innate and acquired behaviors. Clinical data reveal an early impairment of olfaction during normal aging and in the course of neurodegenerative diseases, but the underlying cellular/molecular mechanisms remain obscure. In the current review, we compare different aspects of the aging- and Alzheimer’s disease related impairment of olfaction in men and mice, aiming at the identification of common morbidities and biomarkers, which can be analyzed in detail in the appropriate mouse models. We also identify common, often interdependent (patho)physiological pathways, including but not limited to extracellular amyloid depositions, neuroinflammation, ɛ4 allele of the apolipoprotein E, CNS insulin resistance, and the impairment of adult neurogenesis, to be targeted by basic and clinical research.

9 citations

Journal ArticleDOI
TL;DR: In this article, a possible vicious spiral linking early chronic short sleep, neuronal hyperexcitability, inflammation and neurodegeneration was proposed, which may hold promise for reducing attrition in the late stages of neuroprotective drug development.

7 citations

Journal ArticleDOI
TL;DR: In this paper , the authors reviewed the evidence from mouse models that shows how synchronized oscillatory activity is intricately linked to AD machinery, and they primarily focused on recent reports showing abnormal oscillatory activities at theta and gamma frequencies in AD condition and their influence on cellular disturbances and cognitive impairments.

6 citations

Journal ArticleDOI
TL;DR: Wang et al. as discussed by the authors explored the mechanism of olfactory dysfunction in preclinical AD in the perspective of abnormal neural networks in the Olfactory bulb and the piriform cortex and their associated brain regions, especially from two aspects of aberrant oscillations and synaptic plasticity damages.

6 citations

Journal ArticleDOI
TL;DR: In this article, the authors explore the mechanism of olfactory dysfunction in preclinical AD in the perspective of abnormal neural networks in the Olfactory bulb and the piriform cortex and their associated brain regions, especially from two aspects of aberrant oscillations and synaptic plasticity damages.

6 citations

References
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Journal ArticleDOI
07 Jan 1993-Nature
TL;DR: The best understood form of long-term potentiation is induced by the activation of the N-methyl-d-aspartate receptor complex, which allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and post Synaptic mechanisms to generate a persistent increase in synaptic strength.
Abstract: Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.

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Journal ArticleDOI
31 Jan 2002-Neuron
TL;DR: Theta oscillations represent the "on-line" state of the hippocampus and are believed to be critical for temporal coding/decoding of active neuronal ensembles and the modification of synaptic weights.

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Journal ArticleDOI
TL;DR: The cellular and synaptic mechanisms underlying gamma oscillations are reviewed and empirical questions and controversial conceptual issues are outlined, finding that gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition.
Abstract: Gamma rhythms are commonly observed in many brain regions during both waking and sleep states, yet their functions and mechanisms remain a matter of debate. Here we review the cellular and synaptic mechanisms underlying gamma oscillations and outline empirical questions and controversial conceptual issues. Our main points are as follows: First, gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition. Second, gamma oscillations are short-lived and typically emerge from the coordinated interaction of excitation and inhibition, which can be detected as local field potentials. Third, gamma rhythm typically concurs with irregular firing of single neurons, and the network frequency of gamma oscillations varies extensively depending on the underlying mechanism. To document gamma oscillations, efforts should be made to distinguish them from mere increases of gamma-band power and/or increased spiking activity. Fourth, the magnitude of gamma oscillation is modulated by slower rhythms. Such cross-frequency coupling may serve to couple active patches of cortical circuits. Because of their ubiquitous nature and strong correlation with the "operational modes" of local circuits, gamma oscillations continue to provide important clues about neuronal population dynamics in health and disease.

2,168 citations


"Functional Alterations in the Olfac..." refers background in this paper

  • ...In electrophysiological studies, gamma frequency stimulation bursts repeated at theta frequency effectively induces long-term potentiation, a type of synaptic plasticity in the hippocampal CA1 area [20,62]....

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  • ...The precise spike timing of activated neural networks and the temporal coordination of rhythmic oscillations play a key role in the mechanisms of synaptic plasticity and processes of cognition [19,20]....

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Journal ArticleDOI
TL;DR: Specific immunocytochemical methods (AT8) permit evaluation of neuronal changes well before the actual formation of neurofibrillary tangles and neuropil threads, which facilitates recognition of even subtle pathologic changes throughout the entire extent of cortical territories such as the transentorhinal and entorHinal regions.

2,081 citations

Journal ArticleDOI
TL;DR: CFC might serve as a mechanism to transfer information from large-scale brain networks operating at behavioral timescales to the fast, local cortical processing required for effective computation and synaptic modification, thus integrating functional systems across multiple spatiotemporal scales.

1,701 citations


"Functional Alterations in the Olfac..." refers background in this paper

  • ...The temporal interaction between superimposed network oscillations is considered as a key mechanism facilitating the communication and functional connectivity between distant brain regions required for plasticity and information processing [32,33]....

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  • ...The strength of the PAC index has been shown to correlate with cognitive performance [32,33]....

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