The brain controls the function of neural circuits and networks, in part, by modulating the synchrony of their components.
Network hypersynchrony and altered oscillatory rhythmic activity may underlie cognitive abnormalities in Alzheimer disease (AD).
In AD, network activities that support cognition are altered decades before clinical disease onset, and the affected networks predict future pathology and brain atrophy.
Although the precise causes and pathophysiological consequences of these network alterations remain to be fully elucidated, interneuron dysfunction and network abnormalities have emerged as potential mechanisms of cognitive dysfunction in AD and related disorders.
Several lines of evidence suggest that modulating interneuron-dependent network alterations could be a useful therapeutic strategy to improve brain functions in these conditions.
The function of neural circuits and networks can be controlled, in part, by modulating the synchrony of their components' activities. Network hypersynchrony and altered oscillatory rhythmic activity may contribute to cognitive abnormalities in Alzheimer disease (AD). In this condition, network activities that support cognition are altered decades before clinical disease onset, and these alterations predict future pathology and brain atrophy. Although the precise causes and pathophysiological consequences of these network alterations remain to be defined, interneuron dysfunction and network abnormalities have emerged as potential mechanisms of cognitive dysfunction in AD and related disorders. Here, we explore the concept that modulating these mechanisms may help to improve brain function in these conditions.
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The authors thank P. Sanchez, Y. Huang, A. Kreitzer and members of their laboratories for helpful discussions; S. Ordway for editorial review; and C. Dickerson and A. Cheung for administrative assistance. This work was supported by US National Institutes of Health grants AG011385 (L.M.), AG053981 (L.M.) and AG047313 (J.J.P.); an Alzheimer's Association grant IIRG-13-284779 (J.J.P.); an S.D. Bechtel, Jr. Young Investigator Award (J.J.P.); and a gift from the Dolby Family.
L.M. has received research funding from Bristol-Myers Squibb and Cure Network Dolby Acceleration Partners; he serves on the scientific advisory boards of Acumen Pharmaceuticals, Alkahest, Dolby Family Ventures, E-scape Bio and Neuropore Therapies. J.P. received research funding from Genentech and Cure Network Dolby Acceleration Partners.
FAD mouse models with network hypersynchrony. (PDF 217 kb)
Alterations APP-J20 mice have in common with human AD patients (PDF 198 kb)
Genetic alterations in FAD pedigrees showing network hypersynchrony (PDF 301 kb)
Transformation of acquired information into changes in brain activity. Memory formation requires effective encoding but also involves the storage of the acquired information for later retrieval.
- Preclinical stages
Phases of disease development during which people are still asymptomatic and physicians are not yet able to detect by standard clinical examination the abnormalities that are required for the diagnosis of the disease.
- Oscillatory rhythmic activity
Rhythmic electrical activity that is generated by populations of neurons and contains different frequency bands. Frequency, amplitude (or power) and phase are the basic properties of brain oscillations (or brain rhythms).
- Network hypersynchrony
Pathological state of excessive synchronization of neuronal activities that results in epileptiform discharges or seizures that are detectable by local field recordings or electroencephalography.
- Neuronal synchrony
The degree of correlated neuronal activity within or across populations of neurons; measures to assess neuronal synchrony typically include action potentials or membrane potential fluctuations for single neurons (cellular synchrony), and local field recordings, electroencephalographic recordings or microscopic imaging with activity-dependent sensors for populations of neurons (network synchrony).
- Default mode network
(DMN). Brain regions that show decreased functional MRI signals during attention-demanding tasks and increased functional MRI signals during inwardly oriented mental activity.
- Non-task-related networks
Networks (also known as task-negative networks) that comprise widely distributed brain regions that show decreased functional MRI signals during attention- demanding cognitive tasks.
- Inhibitory interneuron
A type of neuronal cell that typically produces the inhibitory neurotransmitter GABA and regulates the activity of many other neurons, neuronal synchrony and the functional state of brain networks.
- Task-related networks
Networks (also known as task-positive networks) that comprise widely distributed brain regions that show increased functional MRI signals during attention- demanding cognitive tasks.
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Palop, J., Mucke, L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci 17, 777–792 (2016). https://doi.org/10.1038/nrn.2016.141
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