Pharmacological inhibition of PI3-kinase, a lipid kinase involved in the transduction of growth factor receptors and G protein-coupled receptors (GPCR), inhibited long term potentiation (LTP) in the CA1 region and also reversed established potentiation. Consistently, high frequency stimulation (HFS) caused elevation of PI3-kinase activity in the CA1 during post-tetanic potentiation (PTP) and LTP. Increased phosphorylation of the oncogene Akt and p70SK6, which are regulated by PI3-kinase and believed to be two of its main downstream targets, was also observed during PTP and LTP. Also, consistently, inhibition of p70SK6 blocked LTD induction. The PI3-kinase can interact with many of the pathways involved in plasticity with potential for summations and synergisms. Specifically, we propose to investigate the mechanisms of PI3-kinase recruitment in LTP in the CA1 region of the hippocampus. In particular we will explore the role of receptor protein tyrosine kinases and GPCR such as the glutamatergic metabotropic receptors, both of which can recruit PI3-kinases. We also propose to investigate the distribution of PI3-kinase isozymes in the central nervous system with special reference to the hippocampus as well as the translocation of PI3-kinase and its putative effectors such as Akt following HFS and different pharmacological manipulations. At least 4 PI3-kinase catalytic subunits have been described and their distribution in the central nervous system (CNS) is currently poorly understood. Given that the recent evidence suggests that the cellular repertoire of catalytic subunits determines the mechanisms of activation of PI3-kinase, it appears of paramount importance to conduct an anatomical mapping study of PI3-kinase isozymes and regulatory subunits in the CNS. The proposed research will contribute to the understanding of cellular and molecular mechanisms of human memory and possibly to the identification of novel approaches to the prevention and management of the dementias, including Alzheimer disease.
| Izzo, Emanuela; Martin-Fardon, Remi; Koob, George F et al. (2002) Neural plasticity and addiction: PI3-kinase and cocaine behavioral sensitization. Nat Neurosci 5:1263-4 |
| Sanna, Pietro Paolo; Cammalleri, Maurizio; Berton, Fulvia et al. (2002) Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region. J Neurosci 22:3359-65 |
