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R E V I E W S
Certain activities of neurons and neuronal networks are associated with the successful encoding of memories and retention of new information, and thus may be necessary for learning and memory. In Alzheimer disease (AD), schizophrenia, epilepsy and other neurological and psychiatric diseases that cause cognitive impairment, network activities supporting cognition are altered, even during preclinical stages15, that is, before symptoms are noticed by the patient or can be detected by neurocognitive exams. These network alterations include activation and deactivation deficits, abnormal oscillatory rhythmic activity and network hypersynchrony. In people at high risk of developing AD, for example, abnormal activation and deactivation of specific networks during memory encoding can be detected decades before the predicted onset of clinical disease69. As these functional network alterations widely overlap with the brain regions that ultimately develop pathological hallmarks and atrophy in AD, they may be a harbinger and possibly even a cause of clinical disease manifestations.
Robust network alterations are associated with diverse cognitive disorders, but the mechanisms and pathophysiological consequences of the alterations are poorly understood. Do alterations in network activity contribute to cognitive impairment or are they incidental byproducts of diseaseinduced cellular dysfunction? Do alterations in network synchrony cause the dysfunction of microcircuits, larger distributed networks, or both? Most importantly, could cognitive alterations be prevented and even reversed by improving the function of cells that promote specific network activities?
Recent findings suggest that altered network activity can indeed contribute to cognitive impairment in AD and that network activities can be experimentally or behaviourally manipulated to improve cognitive functions in patients at risk of AD and related mouse models. In this Review, we explore two main concepts that network abnormalities and interneuron dysfunction contribute to cognitive deficits in AD and related conditions, and that blocking or counteracting these mechanisms could be of both symptomatic and diseasemodifying therapeuticvalue.
Neuronal synchrony and brain function
Cognitive functions depend on brain states that range from maximal focus and concentration to inattentiveness, drowsiness and sleep. These states probably do not reflect a continuous functional gradient of neuronal activities but rather represent distinct operating modes of brain activity that are closely linked to and possibly determined by changes in neuronal synchrony, the degree to which neuronal activities are...