Abstract
Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity-dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long-term potentiation in the dentate gyrus synapses of the hippocampus. In the present study, to further elucidate the role of IP3K-A in the brain, we developed a transgenic (Tg) mouse line in which IP3K-A is conditionally overexpressed approximately 3-fold in the excitatory neurons of forebrain regions, including the hippocampus. The Tg mice showed an increase in both presynaptic release probability of evoked responses, along with bigger synaptic vesicle pools, and miniature excitatory postsynaptic current amplitude, although the spine density or the expression levels of the postsynaptic density-related proteins NR2B, synaptotagmin 1, and PSD-95 were not affected. Hippocampal-dependent learning and memory tasks, including novel object recognition and radial arm maze tasks, were partially impaired in Tg mice. Furthermore, (R,S)-3,5-dihydroxyphenylglycine-induced metabotropic glutamate receptor long-term depression was inhibited in Tg mice and this inhibition was dependent on protein kinase C but not on the IP3 receptor. Long-term potentiation and depression dependent on N-methyl-d-aspartate receptor were marginally affected in Tg mice. In summary, this study shows that overexpressed IP3K-A plays a role in some forms of hippocampus-dependent learning and memory tasks as well as in synaptic transmission and plasticity by regulating both presynaptic and postsynaptic functions.
Highlights
Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) has emerged as an important molecule for synaptic plasticity owing to its abilities to convert inositol trisphosphate (IP3) to inositol tetrakisphosphate (IP4) as well as to bind to F-actin and microtubules [1,2,3,4,5,6]
The Tg mice were generated using the Tet-On system and reverse tetracycline-controlled transactivator protein was expressed under the control of Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) promoter activation [12]
These results indicated that an IP3K-A Tg mouse line with reversible induction of IP3K-A in the forebrain region was successfully generated
Summary
Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) has emerged as an important molecule for synaptic plasticity owing to its abilities to convert inositol trisphosphate (IP3) to inositol tetrakisphosphate (IP4) as well as to bind to F-actin and microtubules [1,2,3,4,5,6]. Overexpression of IP3K-A in cultured hippocampal neurons promotes dendritic spine formation through Rac interaction and actin remodeling. The N-terminus of IP3K-A can further interact with dendritic microtubules in an activity-dependent manner, and this interaction is inhibited by protein kinase A-dependent phosphorylation of Ser-119 within IP3K-A [4]. The IP3K-A kinase activity, is not essential for either the actin-binding [5] or spine-forming activities of IP3K-A [3]. IP3K-A exerts many physiological effects, including kinase activity-dependent Ca2+ homeostasis and kinase activity-independent neuronal cytoskeletal remodeling
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: 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.