Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage-and Ca 2؉ -activated K ؉ channel (BK channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels (BK ؊/؊ ) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK ؊/؊ mice showed a dramatic reduction in spontaneous activity of the BK ؊/؊ cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia. P otassium channels are the largest and most diverse class of ion channels underlying electrical signaling in the brain (1). By causing highly regulated, time-dependent, and localized polarization of the cell membrane, the opening of K ϩ channels mediates feedback control of excitability in a variety of cell types and conditions (1). Consequently, K ϩ channel dysfunctions can cause a range of neurological disorders (2-6), and drugs that target K ϩ channels hold promise for a variety of clinical applications (7).Among the wide range of voltage-and calcium-gated K ϩ channel types, one stands out as unique: the large-conductance voltage-and Ca 2ϩ -activated K ϩ channel (BK channel, also termed Slo or Maxi-K) differs from all other K ϩ channels in that it can be activated by both intracellular Ca 2ϩ ions and membrane depolarization (8). These channels are widely expressed in central and peripheral neurons, as well as in other tissues (9), and are regarded as a promising drug target (10). However, the functions of the BK channels in vivo have not previously been directly tested in any vertebrate species. We therefore decided to examine the functions of these channels by inactivating the gene encoding the pore-forming channel protein. MethodsA complete description of the methods is given in Supporting Methods, which is published as supporting information on the PNAS web site.Generation of BK Channel ␣ Subunit-Deficient Mice. In the targeting vector (Fig. 5, which is published as supporting information on the PNAS web site), the pore exon was flanked by a single loxP site and a floxed neo͞tk cassette. Correctly targeted embryonic stem cells were injected into C57BL͞6 blastocysts and resulting chimeric mice mated with C57BL͞6. Homozygous BK-deficient mice (F 2 generation) ...

Attempting to understand how the brain, as a whole, might be organized seems, for the ¢rst time, to be a serious topic of inquiry. One aspect of its neuronal organization that seems particularly central to global function is the rich thalamocortical interconnectivity, and most particularly the reciprocal nature of the thalamocortical neuronal loop function. Moreover, the interaction between the speci¢c and non-speci¢c thalamic loops suggests that rather than a gate into the brain, the thalamus represents a hub from which any site in the cortex can communicate with any other such site or sites. The goal of this paper is to explore the basic assumption that large-scale, temporal coincidence of speci¢c and non-speci¢c thalamic activity generates the functional states that characterize human cognition.

Synaptic gain control and information storage in neural networks are mediated by alterations in synaptic transmission, such as in long-term potentiation (LTP). Here, we show using both in vitro and in vivo recordings from the rat cerebellum that tetanization protocols for the induction of LTP at parallel fiber (PF)-to-Purkinje cell synapses can also evoke increases in intrinsic excitability. This form of intrinsic plasticity shares with LTP a requirement for the activation of protein phosphatases 1, 2A, and 2B for induction. Purkinje cell intrinsic plasticity resembles CA1 hippocampal pyramidal cell intrinsic plasticity in that it requires activity of protein kinase A (PKA) and casein kinase 2 (CK2) and is mediated by a downregulation of SK-type calcium-sensitive K conductances. In addition, Purkinje cell intrinsic plasticity similarly results in enhanced spine calcium signaling. However, there are fundamental differences: first, while in the hippocampus increases in excitability result in a higher probability for LTP induction, intrinsic plasticity in Purkinje cells lowers the probability for subsequent LTP induction. Second, intrinsic plasticity raises the spontaneous spike frequency of Purkinje cells. The latter effect does not impair tonic spike firing in the target neurons of inhibitory Purkinje cell projections in the deep cerebellar nuclei, but lowers the Purkinje cell signal-to-noise ratio, thus reducing the PF readout. These observations suggest that intrinsic plasticity accompanies LTP of active PF synapses, while it reduces at weaker, nonpotentiated synapses the probability for subsequent potentiation and lowers the impact on the Purkinje cell output.

Cortical-projecting thalamic neurons, in guinea pig brain slices, display high-frequency membrane potential oscillations (20-80 Hz), when their somata are depolarized beyond ؊45 mV. These oscillations, preferentially located at dendritic sites, are supported by the activation of P͞Q type calcium channels, as opposed to the expected persistent sodium conductance responsible for such rhythmic behavior in other central neurons. Short hyperpolarizing pulses reset the phase and transiently increase the amplitude of these oscillations. This intrinsic thalamic electroresponsiveness may serve as a cellular-based temporal binding mechanism that sharpens the temporal coincidence of cortical-feedback synaptic inputs, known to distribute at remote dendritic sites on thalamic neurons.The intrinsic electrophysiological properties of thalamic neurons are among the richest in the central nervous system (1-3). In addition to the membrane mechanisms responsible for spike generation and synaptic transmission present in most nerve cells, thalamic neurons express several types of voltage-gated sodium, potassium, and calcium conductances that are responsible for the complex excitability patterns that these cells demonstrate (2, 4). High-frequency spontaneous membrane oscillations (near 40 Hz) have been described in projection (5, 6) and reticular thalamic neurons (7). Such near 40 Hz oscillations were originally shown at sparsely spinous interneurons of the frontal cortex where the oscillations are dependent on the activation of a persistent sodium conductance (8). Here we report that in thalamocortical neurons (TCNs), calcium conductances, located preferentially at remote dendritic sites, rather than sodium conductances, are responsible for such high-frequency membrane potential oscillations. A short communication on these results has been presented (9). MATERIALS AND METHODSThe electrophysiological and Ca 2ϩ imaging results reported here were performed in adult guinea pig thalamic slices. Slicing and recording techniques were the same as those used in previous research in this laboratory (1). Briefly, adult guinea pigs (150-250 g) were anesthetized with Nembutal (30 mg͞kg) and decapitated. Using a vibratome, coronal slices (350-400 m), were prepared from a block of tissue containing the thalamus and associated cortex such that thalamocortical connectivity was maintained. The slices were cut under cold (6-10ЊC) oxygenated Ringer's solution, allowed to recover for 1-2 hr, and then transferred to a recording chamber superfused with a solution containing 126 mM NaCl, 5 mM KCl, 26 mM NaHCO 3 , 13 mM MgSO 4 , 12 mM KH 2 PO 4 , and 10 mM glucose saturated with 95% O 2 ͞5% CO 2 . Recordings were performed at 35ЊC. In experiments where the ionic medium was modified, control solutions contained 130 mM NaCl, 6.2 mM KCl, 1.3 mM MgCl 2 , 10 mM glucose, 25 mM Hepes and saturated with 100% O 2 . In the sodium free solutions, NaCl was substituted on equimolar bases by choline chloride. When Cd 2ϩ , Mg 2ϩ , CO 2ϩ , and Ba 2ϩ were added in c...