No abstract

Alzheimer’s disease (AD) and Parkinson’s disease (PD) share many commonalities ranging from signaling deficits such as altered cholinergic activity, neurotrophin and insulin signaling to cell stress cascades that result in proteinopathy, mitochondrial dysfunction and neuronal cell death. These pathological processes are not unidirectional, but are intertwined, resulting in a series of feed-forward loops that worsen symptoms and advance disease progression. At the center of these loops is glycogen synthase kinase-3 (GSK-3), a keystone protein involved in many of the multidirectional biological processes that contribute to AD and PD neuropathology. Here, a unified overview of the involvement of GSK-3 in the major processes involved in these diseases will be presented. The mechanisms by which these processes are linked will be discussed and the feed-forward pathways identified. In this regard, this review will put forth the notion that combination therapy, targeting these multiple facets of AD or PD neuropathology is a necessary next step in the search for effective therapies.

Introduction The dopamine D5 receptor (D5R) shows high expression in cortical regions, yet the role of the receptor in learning and memory remains poorly understood. This study evaluated the impact of prefrontal cortical (PFC) D5R knockdown in rats on learning and memory and assessed the role of the D5R in the regulation of neuronal oscillatory activity and glycogen synthase kinase‐3 (GSK‐3β), processes integral to cognitive function. Materials and Methods Using an adeno‐associated viral (AAV) vector, male rats were infused with shRNA to the D5R bilaterally into the PFC. Local field potential recordings were taken from freely moving animals and spectral power and coherence were evaluated in, and between, the PFC, orbitofrontal cortex (OFC), hippocampus (HIP), and thalamus. Animals were then assessed in object recognition, object location, and object in place tasks. The activity of PFC GSK‐3β, a downstream effector of the D5R, was evaluated. Results AAV‐mediated knockdown of the D5R in the PFC induced learning and memory deficits. These changes were accompanied by elevations in PFC, OFC, and HIP theta spectral power and PFC‐OFC coherence, reduced PFC‐thalamus gamma coherence, and increased PFC GSK‐3β activity. Conclusion This work demonstrates a role for PFC D5Rs in the regulation of neuronal oscillatory activity and learning and memory. As elevated GSK‐3β activity has been implicated in numerous disorders of cognitive dysfunction, this work also highlights the potential of the D5R as a novel therapeutic target via suppression of GSK‐3β.

Background. Alterations in glycogen synthase kinase-3β (GSK-3β) activity have been implicated in disorders of cognitive impairment including Alzheimer’s disease and schizophrenia. Another characteristic of cognitive impairment is the dysregulation of neural oscillatory activity, macroscopic electrical rhythms in brain critical to systems communication. A direct functional relationship between GSK-3β and neural oscillations has not been elucidated.Methods. In the present study, the impact of increasing GSK-3β activity in prefrontal cortex (PFC) or hippocampus (HIP) on the regulation of neural oscillations in rats was investigated using an adeno-associated viral vector containing a persistently active mutant of GSK-3β (S9A), and changes in learning and memory and tau phosphorylation assessed.Results. Increasing GSK-3β activity in either region had similar effects on oscillatory spectral power, enhancing theta and/or gamma oscillatory power recorded from one or both regions. Increasing PFC GSK-3β activity additionally suppressed high gamma PFC-HIP coherence. These oscillatory changes were accompanied by deficits in recognition memory, spatial learning and/or reversal learning. Increased pathogenic tau phosphorylation was also evident in regions where GSK-3β activity was elevated. Conclusions. These findings indicate that increased GSK-3β activity in PFC or HIP dysregulates neural oscillatory function in, and between, these regions. This suggests that GSK-3β may not only play an early role in cognitive decline in Alzheimer’s disease but may also play a more central role in disorders of cognitive dysfunction through the regulation of neurophysiological network function.