Year-end Sale % OFF 
Abstract
Deregulation of GSK‐3β is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. To understand how GSK‐3β becomes dysregulated in these conditions, it is important to understand its physiological functions in the central nervous system. In this context, GSK‐3β plays a role in the induction of NMDA receptor‐dependent long‐term depression (LTD) and several substrates for GSK‐3β have been identified in this form of synaptic plasticity, including KLC‐2, PSD‐95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK‐3β, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK‐3β substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα has no effect on synaptic AMPA receptor‐mediated synaptic transmission but substantially reduces NMDA receptor‐mediated synaptic transmission. Furthermore, the ability of the selective GSK‐3 inhibitor, CT99021, to reduce the amplitude of NMDA receptor‐mediated currents was occluded in shRNA‐PI4KIIα transfected neurons. The effects of knocking down PI4KIIα were fully rescued by a shRNA‐resistant wild‐type construct, but not by a mutant construct that cannot be phosphorylated by GSK‐3β. These data suggest that GSK‐3β phosphorylates PI4KIIα to stabilize NMDA receptors at the synapse.
Highlights
NMDA receptors are important for both synaptic transmission (Herron et al, 1986) and synaptic plasticity in the hippocampus (Collingridge et al, 1983)
These were an shRNA probe to reduce the expression of phosphatidylinositol 4 kinase type IIα (PI4KIIα) and two shRNA resistant constructs for rescue experiments; a wild-type (WT) and a mutant PI4KIIα (S9/51A) that cannot be phosphorylated by GSK-3β
In the same neurons recorded at +40 mV, knockdown of PI4KIIα led to a significant reduction in the EPSC recorded at a latency of 60 ms, at a time when the response is dominated by an NMDA receptor-mediated component (EPSC-N) (Fig 1B)
Summary
NMDA receptors are important for both synaptic transmission (Herron et al, 1986) and synaptic plasticity in the hippocampus (Collingridge et al, 1983). We found that the activation of GSK-3β is involved in NMDA receptordependent long-term depression (LTD) (Peineau et al, 2007), a form of synaptic plasticity that involves the endocytosis of AMPA receptors and is involved in developmental plasticity and learning and memory (Collingridge et al, 2010). In addition to regulating downstream effectors of the LTD process, GSK-3β has been shown to regulate NMDA receptor function (Chen et al, 2007). This process involves regulation of the GDI:Rab complex, as well as dynamin and disruption of the binding of NMDA receptors to PSD-95
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
