Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP

Coincident pre- and postsynaptic activity generates long-term potentiation (LTP), a possible cellular model of learning and memory. LTP has two compon ents: (1) an increase in the excitatory postsynaptic potential (EPSP), and (2) an increase in the ability of the EPSP to generate a spike (ES coupling of LTP). We have used pharmacological and genetic approaches to address th e molecular nature of E-S coupling in CA1 pyramidal neurons. Blockade of th e Ca2+-sensitive phosphatase, calcineurin, prevents induction of ES couplin g without interfering with LTP of the EPSP. Calcineurin produces its effect on E-S coupling by inducing a long-lasting depression (LTD) of the GABA,me diated inhibitory postsynaptic potentials (IPSPs). This LTD of the IPSP was prevented by blockade of NMDA receptors. Thus, the tetanus that elicits NM DA-dependent LTP mediates a coordinately regulated double function. It prod uces LTP of the EPSP and, concomitantly, LTD of the IPSP that leads to enha ncement of E-S coupling.