Homeostatic regulation of synaptic excitability: Tonic GABAA receptor currents replace Ih in cortical pyramidal neurons of HCN1 knock-out mice

Abstract

Homeostatic control of synaptic efficacy is often mediated by dynamic regulation of excitatory synaptic receptors. Here, we report a novel form of homeostatic synaptic plasticity based on regulation of shunt currents that control dendritosomatic information transfer. In cortical pyramidal neurons from wild-type mice, HCN1 channels underlie a dendritic hyperpolarization-activated cationic current (Ih ) that serves to limit temporal summation of synaptic inputs. In HCN1 knock-out mice, as expected, Ih is reduced in pyramidal neurons and its effects on synaptic summation are strongly diminished. Unexpectedly, we found a markedly enhanced bicuculline- and L-655,708-sensitive background GABAA current in these cells that could be attributed to selective upregulation of GABAA α5 subunit expression in the cortex of HCN1 knock-out mice. Strikingly, despite diminished Ih , baseline sublinear summation of evoked EPSPs was unchanged in pyramidal neurons fromHCN1knock-out mice; however, blocking tonicGABAA currents with bicuculline enhanced synaptic summation more strongly in pyramidal cells from HCN1 knock-out mice than in those cells from wild-type mice. Increasing tonic GABAA receptor conductance in the context of reduced Ih , using computational or pharmacological approaches, restored normal baseline synaptic summation, as observed in neurons from HCN1 knock-out mice. These data indicate that upregulation of α5 subunit-mediated GABAA receptor tonic current compensates quantitatively for loss of dendritic Ih in cortical pyramidal neurons from HCN1 knock-out mice to maintain normal synaptic summation; they further imply that dendritosomatic synaptic efficacy is a controlled variable for homeostatic regulation of cortical neuron excitability in vivo. Copyright © 2010 the authors.