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The Journal of Neuroscience, May 1, 2002, 22(9):3359-3365

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

Pietro Paolo Sanna¹, Maurizio Cammalleri^{1, 2}, Fulvia Berton^{1, 2}, Cindy Simpson¹, Robert Lutjens¹, Floyd E. Bloom¹, and Walter Francesconi^{1, 2}

¹ Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, and ² Universita' degli Studi Di Pisa, Dipartimento di Fisiologia e Biochimica "G. Moruzzi", Pisa, Italy 56127

Several signal transduction pathways have been implicated in the induction of long-term potentiation (LTP), yet the signal transduction mechanisms behind the maintenance-expression phase of LTP are still poorly understood. We investigated the role of phosphatidylinositol 3-kinase (PI3-kinase) in LTP at Schaffer collateral/commissural fiber-CA1 synapses in rat hippocampal slices using biochemical approaches and extracellular electrophysiological recordings. We observed that PI3-kinase activity was induced in the CA1 region during LTP of field EPSPs (fEPSPs) and that two structurally unrelated PI3-kinase inhibitors, LY294002 and wortmannin, abated established LTP, suggesting that PI3-kinase is involved in the maintenance-expression phase of LTP. However, LTP recovered after washout of the reversible PI3-kinase inhibitor LY294002, confirming that LTP maintenance and expression are distinct events and indicating that PI3-kinase activity is required for LTP expression rather than for its maintenance. Interestingly, preincubation with LY294002 did not prevent LTP induction. In fact, if LY294002 was withdrawn 5 min after high-frequency stimulation, an LTP of fEPSP was seen. Last, a voltage-dependent calcium channel-dependent form of LTP in the CA1 could also be reversibly abated by LY294002, raising the possibility that PI3-kinase could be required for the expression of multiple forms of synaptic potentiation.

Key words: long-term potentiation; synaptic plasticity; hippocampus; PI3-kinase; signal transduction; NMDA; voltage-dependent calcium channels; AMPA

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2293359-07$05.00/0

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