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

Abstract : Key points r We determined the contribution of the hyperpolarization-activated cationic (h) current (I h) to the homeostatic regulation of CA1 pyramidal cells in vitro using chronic treatments (48 h) that either increase (picrotoxin) or decrease (kynurenate) neuronal activity. r The h-conductance was found to be up-or down-regulated following chronic activity enhancement or activity deprivation, respectively. This bidirectional plasticity of I h was found to subsequently alter both apparent input resistance and intrinsic neuronal excitability. r Bidirectional homeostatic plasticity of I h also determined EPSP waveform and EPSP summation tested at 5–30 Hz. r Long-term synaptic modification induced by repetitive stimulation of the Schaffer collaterals was found to be constant across treatments in the presence of I h but not when I h was blocked pharmacologically. Thus, bidirectional homeostatic regulation of I h stabilizes induction of long-term synaptic modification in CA1 pyramidal neurons that depends on EPSP summation. Abstract 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 (2–3 days) 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 hyper-activity 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 3–10 Hz 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.
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Célia Gasselin, Yanis Inglebert, Dominique Debanne. Homeostatic regulation of h-conductance controls intrinsic excitability and stabilizes the threshold for synaptic modification in CA1 neurons. The Journal of Physiology, Wiley, 2015, 593 (22), pp.4855-4869. ⟨10.1113/JP271369⟩. ⟨hal-01766843⟩

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