Excitatory Pathways from the Lateral Habenula Enable Propofol-Induced Sedation.

The lateral habenula has been widely studied for its contribution in generating reward-related behaviors [1, 2]. We have found that this nucleus plays an unexpected role in the sedative actions of the general anesthetic propofol. The lateral habenula is a glutamatergic, excitatory hub that projects to multiple targets throughout the brain, including GABAergic and aminergic nuclei that control arousal [3-5].

Fast and Slow Inhibition in the Visual Thalamus Is Influenced by Allocating GABA Receptors with Different γ Subunits.

Cell-type specific differences in the kinetics of inhibitory postsynaptic conductance changes (IPSCs) are believed to impact upon network dynamics throughout the brain. Much attention has focused on how GABA receptor (GABAR) α and β subunit diversity will influence IPSC kinetics, but less is known about the influence of the γ subunit. We have examined whether GABAR γ subunit heterogeneity influences IPSC properties in the thalamus.

Exploring the significance of morphological diversity for cerebellar granule cell excitability.

The relatively simple and compact morphology of cerebellar granule cells (CGCs) has led to the view that heterogeneity in CGC shape has negligible impact upon the integration of mossy fibre (MF) information. Following electrophysiological recording, 3D models were constructed from high-resolution imaging data to identify morphological features that could influence the coding of MF input patterns by adult CGCs. Quantification of MF and CGC morphology provided evidence that CGCs could be connected to the multiple rosettes that arise from a single MF input.

The contribution of δ subunit-containing GABAA receptors to phasic and tonic conductance changes in cerebellum, thalamus and neocortex.

We have made use of the δ subunit-selective allosteric modulator DS2 (4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridine-3-yl benzamide) to assay the contribution of δ-GABAARs to tonic and phasic conductance changes in the cerebellum, thalamus and neocortex. In cerebellar granule cells, an enhancement of the tonic conductance was observed for DS2 and the orthosteric agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol). As expected, DS2 did not alter the properties of GABAA receptor-mediated inhibitory postsynaptic synaptic conductances (IPSCs) supporting a purely extrasynaptic role for δ-GABAARs in cerebellar granule cells.

Disrupting the clustering of GABAA receptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits.

In schizophrenia, cognitive dysfunction is highly predictive of poor patient outcomes and is not responsive to current medications. Postmortem studies have suggested that cognitive deficits in schizophrenia are correlated with modifications in the number and size of inhibitory synapses. To test if these modifications lead to cognitive deficits, we have created a dominant-negative virus [adeno-associated (AAV)-DN1] that disrupts the clustering of γ-aminobutyric acid type A receptors (GABA(A)Rs) at postsynaptic inhibitory specializations.

Copper block of extrasynaptic GABAA receptors in the mature cerebellum and striatum.

Inhibition of GABAA receptors by Cu(2+) has been appreciated for some time, but differences between synaptic and extrasynaptic GABAA receptors have not been explored. We show that Cu(2+) potently blocks steady-state GABA currents mediated by extrasynaptic δ subunit-containing GABAA receptors (δ-GABAARs) with an IC50 of 65 nM. This compares with an IC50 of 85 μM for synaptic γ subunit-containing GABAARs (γ-GABAARs).

Are extrasynaptic GABAA receptors important targets for sedative/hypnotic drugs?

High-affinity extrasynaptic GABA(A) receptors are persistently activated by the low ambient GABA levels that are known to be present in extracellular space. The resulting tonic conductance generates a form of shunting inhibition that is capable of altering cellular and network behavior. It has been suggested that this tonic inhibition will be enhanced by neurosteroids, antiepileptics, and sedative/hypnotic drugs.

Deficits in spatial memory correlate with modified {gamma}-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus.

Fast synaptic inhibition in the brain is largely mediated by gamma-aminobutyric acid receptors (GABA(A)R). While the pharmacological manipulation of GABA(A)R function by therapeutic agents, such as benzodiazepines can have profound effects on neuronal excitation and behavior, the endogenous mechanisms neurons use to regulate the efficacy of synaptic inhibition and their impact on behavior remains poorly understood. To address this issue, we created a knock-in mouse in which tyrosine phosphorylation of the GABA(A)Rs gamma2 subunit, a posttranslational modification that is critical for their functional modulation, has been ablated.

Intracellular chloride ions regulate the time course of GABA-mediated inhibitory synaptic transmission.

The time-dependent integration of excitatory and inhibitory synaptic currents is an important process for shaping the input-output profiles of individual excitable cells, and therefore the activity of neuronal networks. Here, we show that the decay time course of GABAergic inhibitory synaptic currents is considerably faster when recorded with physiological internal Cl(-) concentrations than with symmetrical Cl(-) solutions. This effect of intracellular Cl(-) is due to a direct modulation of the GABA(A) receptor that is independent of the net direction of current flow through the ion channel.

CaMKII phosphorylation of the GABA(A) receptor: receptor subtype- and synapse-specific modulation.

As a major inhibitory neurotransmitter, GABA plays a vital role in the brain by controlling the extent of neuronal excitation. This widespread role is reflected by the ubiquitous distribution of GABA(A) receptors throughout the central nervous system. To regulate the level of neuronal inhibition requires some endogenous control over the release of GABA and/or its postsynaptic response.

Distinct regulation of beta2 and beta3 subunit-containing cerebellar synaptic GABAA receptors by calcium/calmodulin-dependent protein kinase II.

Modulation of GABA(A) receptor function and inhibitory synaptic transmission by phosphorylation has profound consequences for the control of synaptic plasticity and network excitability. We have established that activating alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMK-II) in cerebellar granule neurons differentially affects populations of IPSCs that correspond to GABA(A) receptors containing different subtypes of beta subunit. By using transgenic mice, we ascertained that alpha-CaMK-II increased IPSC amplitude but not the decay time by acting via beta2 subunit-containing GABA(A) receptors.

Identification of the sites for CaMK-II-dependent phosphorylation of GABA(A) receptors.

Phosphorylation can affect both the function and trafficking of GABA(A) receptors with significant consequences for neuronal excitability. Serine/threonine kinases can phosphorylate the intracellular loops between M3-4 of GABA(A) receptor beta and gamma subunits thereby modulating receptor function in heterologous expression systems and in neurons (1, 2). Specifically, CaMK-II has been demonstrated to phosphorylate the M3-4 loop of GABA(A) receptor subunits expressed as GST fusion proteins (3, 4).