E-S potentiation has been reported to depend on disinhibition ( Abraham et al., 1987 Chavez-Noriega et al., 1990), but later studies have suggested a change in the intrinsic excitability ( Wathey et al., 1992 Pugliese et al., 1994 Jester et al., 1995 Wang et al., 2003). In CA1 hippocampal pyramidal neurons, after induction of LTP, postsynaptic spike firing increases more than would be expected from synaptic LTP, a phenomenon referred to as EPSP-to-spike (E-S) potentiation ( Bliss and Lomo, 1973 Andersen et al., 1980). In contrast to the detailed analysis of synaptic long-term potentiation (LTP), a cellular model for learning and memory ( Bliss and Collingridge, 1993 Malenka and Nicoll, 1999 Choi et al., 2000), less attention has been given to activity-dependent changes in the intrinsic excitability of neurons. The intrinsic excitability of neurons has a crucial impact on the function of neural networks and is modified during the learning task in a variety of species ( Alkon et al., 1985 Cleary et al., 1998 Antonov et al., 2001 Burrell et al., 2001 Aizenman et al., 2003). This new form of hippocampal neuronal plasticity could be a cellular correlate of learning and memory besides synaptic LTP. The results suggest that induction of LTP-IE shares a similar signaling pathway with the late phase of synaptic LTP and requires activation of the NMDA glutamate receptor subtype, Ca 2+ influx, activity of CaM kinase II, and function of the protein synthesis. Induction of LTP-IE was blocked by the NMDA receptor antagonist APV, intracellular BAPTA, the CaM kinase inhibitors KN-62 and autocamtide-2-related inhibitory peptide, and the protein synthesis inhibitors emetine and anisomycin. Cell-attached patch recording of VGSC activities indicated such an activity-dependent change in VGSCs. LTP-IE was manifested as a decrease in the action potential threshold that was attributable to a hyperpolarized shift in the activation curve of voltage-gated sodium channels (VGSCs) rather than activity-dependent changes in synaptic inputs or A-type K + channels. By stimulating hippocampal CA1 pyramidal neurons with synaptic inputs correlating with postsynaptic neuronal spikes, we elicited an LTP of intrinsic excitability (LTP-IE) concurring with synaptic LTP.

In contrast to the detailed analysis of long-term potentiation (LTP), less attention has been given to activity-dependent changes in the intrinsic neuronal excitability. The efficiency of neural circuits is enhanced not only by increasing synaptic strength but also by increasing intrinsic excitability.

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