Homeostatic regulation of h-conductance controls intrinsic excitability and stabilizes the threshold for synaptic modification in CA1 neurons

The hyperpolarization-activated cationic (h) current is a voltage-shock absorber, highly expressed in the dendrites of CA1 pyramidal neurons. Up-regulation of I-h has been reported following episodes of intense network activity but the effect of activity deprivation on I-h and the functional consequence of homeostatic regulation of I-h remain unclear. We determined here the contribution of I-h to the homeostatic regulation of CA1 pyramidal cell excitability. Intrinsic neuronal excitability was decreased in neurons treated for 2-3 days with the GABA(A) channel blocker picrotoxin (PiTx) but increased in neurons treated (2-3days) with the glutamate receptor antagonist kynurenate (Kyn). Membrane capacitance remained unchanged after treatment but the apparent input resistance was reduced for PiTx-treated neurons and enhanced for Kyn-treated neurons. Maximal I-h conductance was up-regulated after chronic hyperactivity but down-regulated following chronic hypoactivity. Up-regulation of I-h in PiTx-treated cultures was found to accelerate EPSP kinetics and reduce temporal summation of EPSPs whereas opposite effects were observed in Kyn-treated cultures, indicating that homeostatic regulation of I-h may control the induction of synaptic modification depending on EPSP summation. In fact, stimulation of the Schaffer collaterals at 3-10Hz induced differential levels of plasticity in PiTx-treated and Kyn-treated neurons when I-h was blocked pharmacologically but not in control conditions. These data indicate that homeostatic regulation of I-h normalizes the threshold for long-term synaptic modification that depends on EPSP summation. In conclusion, bidirectional homeostatic regulation of I-h not only controls spiking activity but also stabilizes the threshold for long-term potentiation induced in CA1 pyramidal neurons by repetitive stimulation.