Alzheimer disease (AD) is associated with an abnormal brain activity common to other brain disorders. Recent observations indicate that neuronal overexcitability manifests during early stages of Alzheimer’s disease. This neuronal hyperexcitability leads to neocortical and hippocampal hyperactivity, impaired network oscillations and under certain conditions, to epileptiform activity and seizures both in mice and humans. Although supporting experimental evidence continue to accumulate, the pathological mechanisms underlying this neuronal hyperactivity remain elusive. Several hypotheses have emerged on the origin of this excessive neuronal activity with the most prominent implicating an amyloid-β mediated disruption of GABAA transmission. Hence, the objective of this project is to test whether several AD-related symptoms can be prevented or attenuated by reversing the deficits in GABAA-mediated inhibition in AD.
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Aging is the most impactful risk factor for neurodegeneration. However, given that in elderly populations neurodegeneration is common and that in very old individuals cognitive decline is prominent, one could argue that neurodegenerative disorders are a manifestation of accelerated aging. Yet, the mechanisms underlying age-related cognitive decline and senile dementia are distinct to the mechanisms inducing Alzheimer's disease (the most common neurodegenerative disorder). Thus, this project aims to understand which are the specific changes in synaptic transmission associated with aging-related neurodegeneration and cognitive decline.
Induced hippocampal hyperactivity in transgenic mouse lines carrying mutations liked with AD have been shown to increase significantly the amyloid-β deposition in the hippocampus. In addition, neuronal hyperactivity seems to contribute to the circuit disfunction occurring in early stages of AD. However, it still remains unknown which is the effect of this neuronal hyperactivity overall in the protein expression and whether some of these proteome alterations could contribute to the facilitation of the hyperactivity and the over-production of amyloid-β in AD.
In vivo and in vitro optogenetics; in vivo electrophysiology; in vivo and ex vivo cellular calcium and chloride imaging; cognitive and social behavioral measurements; immunoblots; immunohistochemistry; single neuron morphology reconstruction