GSK-3 disruption of neuronal firing synchrony in cortex and hippocampus: A new therapeutic approach
University of Toronto
There exists a strong relationship between the coordinated activity of neural networks in specific regions of the brain, such as cortex and hippocampus, with learning and memory. Cognitive decline in Alzheimer’s disease (AD) is accompanied by a dysregulation in this synchronous neuronal oscillatory activity. Yet, uncovering the molecular signaling deficits that contribute to early changes in neuronal oscillations in AD has proven elusive. Glycogen synthase kinase-3 (GSK-3), a protein that shows upregulated activity in cortex and hippocampus of persons with AD, and which is critical to the pathology of the disease, has been widely shown to negatively impact cognitive performance. Unfortunately GSK-3 inhibition is not a viable treatment option in humans due to the potential for adverse effects as a result of its multitude of actions and widespread distribution. However, a more targeted approach may be feasible through activation of the dopamine D5 receptor, which exhibits uniquely high expression in cortex and hippocampus and lower expression elsewhere, and which we showed to inhibit GSK-3 activity. Our research program will first use an animal model to evaluate causality between enhanced cortical and hippocampal GSK-3 activity, neuronal oscillatory deficits, cognitive dysfunction and biochemical changes in brain that are associated with AD. We will also examine a role for the dopamine D5 receptor in the regulation of neuronal oscillations and cognition, a novel candidate for targeted reductions in GSK-3 activity in regions associated with AD neuropathology.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Characterization of how oscillatory deficits develop and change over time in response to increased GSK-3 activity is crucial to better understand the temporal relationship between these events in AD. Furthermore, as widespread GSK-3 inhibition is not a viable treatment option in humans due to the potential for adverse effects, the circumscribed expression of the D5 receptor in cortex and hippocampus makes this receptor an ideal candidate for targeted reductions in GSK-3 activity in AD. Many of the findings will be directly translatable into humans by measurement of EEG in patients and thus understanding the time-dependent changes that occur in these oscillations may allow for identification of a neuronal signature or biomarker for early screening of patients at risk of developing the disease.
Neural network synchrony deficits play an integral role in the pathology of AD. We anticipate that our program will provide an essential framework for the development of novel avenues of research and identification of therapeutic targets, such as the dopamine D5 receptor, with the goal of normalizing neuronal oscillatory deficits early on in the disease process, thus reversing or delaying the onset of disease symptoms.