6-cyano-7-nitroquinoxaline-2-3-dione and tetrahydrodeoxycorticosterone

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) alpha5 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 alpha5 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.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Anti-Anxiety Agents; Bicuculline; Cerebral Cortex; Cyclic Nucleotide-Gated Cation Channels; Desoxycorticosterone; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Female; GABA Agents; Homeostasis; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Neurological; Patch-Clamp Techniques; Potassium Channels; Protein Subunits; Pyramidal Cells; Pyridazines; Pyrimidines; Receptors, GABA-A; Sodium Channel Blockers; Synapses; Tetrodotoxin; Up-Regulation; Valine

Fast inhibitory synaptic transmission is primarily mediated by synaptically released gamma-aminobutyric acid (GABA) acting on postsynaptic GABA(A) receptors. GABA acting on GABA(A) receptors produces not only phasic but also tonic inhibitions by persistent activation of extrasynaptic receptors. However, the mechanistic characteristics of tonic inhibition in the neocortex are not well-understood. To address this, we studied pharmacologically isolated GABA(A) receptor-mediated currents in neocortical pyramidal neurons in rat brain slices. Bath application of bicuculline blocked miniature inhibitory postsynaptic currents (mIPSCs) and produced an outward shift in baseline holding current (I(hold)). Low concentrations of SR95531, a competitive GABA(A) receptor antagonist, abolished mIPSCs but had no significant effect on I(hold). The benzodiazepine midazolam produced an inward shift in I(hold) by augmenting tonic GABA(A) receptor-mediated currents, which were significantly greater in layer V neurons than in layer II/III. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a relatively higher expressions of alpha1 and alpha5 subunit mRNA in layer V neurons. L-655708, an alpha5 subunit-specific inverse agonist, reduced tonic currents in layer V but not in layer II/III neurons, whereas zolpidem, an alpha1-subunit agonist, exerted equivalent effects in both layers. These data suggest that the alpha1 GABA(A) receptor subunit is generally involved in tonic inhibition in pyramidal neurons of the neocortex, whereas the alpha5 subunit is specifically involved in layer V neurons.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Benzodiazepines; Desoxycorticosterone; GABA Agonists; GABA Modulators; Imidazoles; In Vitro Techniques; Midazolam; Neocortex; Neurons; Patch-Clamp Techniques; Pyramidal Cells; Pyridines; Rats; Rats, Wistar; Receptors, GABA-A; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatosensory Cortex; Zolpidem