Kv3.1-Kv3.2 channels underlie a high-voltage-activating component of the delayed rectifier K+ current in projecting neurons from the globus pallidus.

The globus pallidus plays central roles in the basal ganglia circuitry involved in movement control as well as in cognitive and emotional functions. There is therefore great interest in the anatomic and electrophysiological characterization of this nucleus. Most pallidal neurons are GABAergic projecting cells, a large fraction of which express the calcium binding protein parvalbumin (PV). Here we show that PV-containing pallidal neurons coexpress Kv3. 1 and Kv3.2 K+ channel proteins and that both Kv3.1 and Kv3.2 antibodies coprecipitate both channel proteins from pallidal membrane extracts solubilized with nondenaturing detergents, suggesting that the two channel subunits are forming heteromeric channels. Kv3.1 and Kv3.2 channels have several unusual electrophysiological properties when expressed in heterologous expression systems and are thought to play special roles in neuronal excitability including facilitating sustained high-frequency firing in fast-spiking neurons such as interneurons in the cortex and the hippocampus. Electrophysiological analysis of freshly dissociated pallidal neurons demonstrates that these cells have a current that is nearly identical to the currents expressed by Kv3.1 and Kv3.2 proteins in heterologous expression systems, including activation at very depolarized membrane potentials (more positive than -10 mV) and very fast deactivation rates. These results suggest that the electrophysiological properties of native channels containing Kv3.1 and Kv3.2 proteins in pallidal neurons are not significantly affected by factors such as associated subunits or postranslational modifications that result in channels having different properties in heterologous expression systems and native neurons. Most neurons in the globus pallidus have been reported to fire sustained trains of action potentials at high-frequency. Kv3.1-Kv3.2 voltage-gated K+ channels may play a role in helping maintain sustained high-frequency repetitive firing as they probably do in other neurons.

Contributions of Kv3 channels to neuronal excitability.

Four mammalian Kv3 genes have been identified, each of which generates, by alternative splicing, multiple protein products differing in their C-terminal sequence. Products of the Kv3.1 and Kv3.2 genes express similar delayed-rectifier type currents in heterologous expression systems, while Kv3.3 and Kv3.4 proteins express A-type currents. All Kv3 currents activate relatively fast at voltages more positive than -10 mV, and deactivate very fast. The distribution of Kv3 mRNAs in the rodent CNS was studied by in situ hybridization, and the localization of Kv3.1 and Kv3.2 proteins has been studied by immunohistochemistry. Most Kv3.2 mRNAs (approximately 90%) are present in thalamic-relay neurons throughout the dorsal thalamus. The protein is expressed mainly in the axons and terminals of these neurons. Kv3.2 channels are thought to be important for thalamocortical signal transmission. Kv3.1 and Kv3.2 proteins are coexpressed in some neuronal populations such as in fast-spiking interneurons of the cortex and hippocampus, and neurons in the globus pallidus. Coprecipitation studies suggest that in these cells the two types of protein form heteromeric channels. Kv3 proteins appear to mediate, in native neurons, similar currents to those seen in heterologous expression systems. The activation voltage and fast deactivation rates are believed to allow these channels to help repolarize action potentials fast without affecting the threshold for action potential generation. The fast deactivating current generates a quickly recovering after hyperpolarization, thus maximizing the rate of recovery of Na+ channel inactivation without contributing to an increase in the duration of the refractory period. These properties are believed to contribute to the ability of neurons to fire at high frequencies and to help regulate the fidelity of synaptic transmission. Experimental evidence has now become available showing that Kv3.1-Kv3.2 channels play critical roles in the generation of fast-spiking properties in cortical GABAergic interneurons.

Effects of a Ginkgo biloba extract on two models of cortical hemiplegia in rats.

To screen drugs potentially useful in the pharmacological treatment of subjects with brain lesions, we studied the effects of chronic (7 and 30 days) treatments with a Ginkgo biloba extract (EGb761-IPSEN; EGb) in two animal models of cortical hemiplegia: one induced by motor cortex aspiration and another using a reversible inactivation of the motor cortex through chronic, localized infusion of y-aminobutyric acid (GABA), via osmotic minipumps. The elevated beam test was used in water-deprived animals trained to drink saccharin-sweetened solutions (with or without EGb) and to perform to criteria before the surgical procedures. From the day after surgery, the rats were administered 100 mg/kg of EGb daily for 7 or 30 days. In all groups with motor impairment in which the extract was administered, a faster and more complete recovery was observed, which was significantly different from that of rats which received only saccharin solutions. The salutary effect of EGb was more marked in ablation-induced hemiplegia than in the GABA-treated group. In the former injury model, EGb-treated animals had smaller ventricular diameters than non-treated rats. No differences concerning sensory deficits were detected among groups. EGb was also acutely administered during the epileptic syndrome that follows interruption of chronic GABA infusions (the GABA-withdrawal syndrome). No anticonvulsant effects of EGb were observed. These results suggest a potential use of EGb in brain-injured patients as this product shows little toxicity in animals and man after chronic administration. The active principles among terpenes (ginkgolides, bilobalides and flavonolheterosides present in the EGb) and the mechanisms for this beneficial effects remain to be elucidated.