Homeostatic Regulation of Synaptic Excitability: Tonic GABA_AReceptor Currents ReplaceI_hin 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 (I h ) that serves to limit temporal summation of synaptic inputs. In HCN1 knock-out mice, as expected, I h 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 GABA A current in these cells that could be attributed to selective upregulation of GABA A ␣5 subunit expression in the cortex of HCN1 knock-out mice. Strikingly, despite diminished I h , baseline sublinear summation of evoked EPSPs was unchanged in pyramidal neurons from HCN1 knock-out mice; however, blocking tonic GABA A 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 GABA A receptor conductance in the context of reduced I h , 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 ␣5 subunit-mediated GABA A receptor tonic current compensates quantitatively for loss of dendritic I h 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.

Homeostasis of functional maps in active dendrites emerges in the absence of individual channelostasis

“…4 and 5). We also noted this to be consistent with observations from experiments, using either genetic or pharmacological elimination of channels, that blocking specific conductances results in variable effects on physiological measurements used in this study (18)(19)(20)(29)(30)(31)(32)(33)(34)(35).…”

Synaptic and Intrinsic Balancing during Postnatal Development in Rat Pups Exposed to Valproic Acidin Utero

“…Indeed, a number of examples of this sort have been identified, following genetic manipulations. To cite one, a reduction of dendritic H currents by HCN1 gene deletion is met by an increase in background GABA A currents through a selective upregulation of GABA A ␣5 subunit expression (Chen et al, 2010). The compensation is such that layer 5 pyramidal neurons of HCN1-knock-out mice exhibit normal synaptic summation, even though summation in wild-type neurons depends critically on the H current.…”

In Vivo Dynamic Clamp Study of Ih in the Mouse Inferior Colliculus

“…Changes in driving force are considerable for the mixed cation channel I h , which has a reversal potential ϳ20 mV from the resting potential. Moreover, with this approach, it is possible to study the acute effects in a single cell, thus avoiding possible compensatory developmental or network effects that can accompany transgenic studies (Chen et al 2010). By interspersing the presentations with and without the dynamic clamp, very small effects (Ͻ1 mV) could be picked up, even when variability between cells was much larger.…”