Inhibition of Ca2+-activated large-conductance K+ channel activity alters synaptic AMPA receptor phenotype in mouse cerebellar stellate cells.
ABSTRACT Many fast-spiking inhibitory interneurons, including cerebellar stellate cells, fire brief action potentials and express α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors (AMPAR) that are permeable to Ca(2+) and do not contain the GluR2 subunit. In a recent study, we found that increasing action potential duration promotes GluR2 gene transcription in stellate cells. We have now tested the prediction that activation of potassium channels that control the duration of action potentials can suppress the expression of GluR2-containing AMPARs at stellate cell synapses. We find that large-conductance Ca(2+)-activated potassium (BK) channels mediate a large proportion of the depolarization-evoked noninactivating potassium current in stellate cells. Pharmacological blockade of BK channels prolonged the action potential duration in postsynaptic stellate cells and altered synaptic AMPAR subtype from GluR2-lacking to GluR2-containing Ca(2+)-impermeable AMPARs. An L-type channel blocker abolished an increase in Ca(2+) entry that was associated with spike broadening and also prevented the BK channel blocker-induced switch in AMPAR phenotype. Thus blocking BK potassium channels prolongs the action potential duration and increases the expression of GluR2-containing receptors at the synapse by enhancing Ca(2+) entry in cerebellar stellate cells.
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ABSTRACT: In the preceding paper, we showed that norepinephrine (NE) enhances the spontaneous spike firings in cerebellar interneurons, basket cells (BCs), resulting in an increase in the frequency of BC-spike-triggered inhibitory postsynaptic currents (IPSCs) in Purkinje cells (PCs), and that the effects of NE on GABAergic BCs are mediated by beta(2)-adrenergic receptors. This study aimed to further examine the ionic mechanism underlying the beta-adrenoceptor-mediated facilitation of GABAergic transmission at the BC-PC synapses. Using cerebellar slices obtained from 15- to 21-day-old rats and whole cell recordings, we investigated ionic currents in the BCs and the effects of the beta-agonist isoproterenol (ISP) as well as forskolin on the BC excitability. Hyperpolarizing voltage steps from a holding potential of -50 mV elicited a hyperpolarization-activated inward current, I(h), in the BC. This current exhibited voltage-dependent activation that was accelerated by strong hyperpolarization, displaying two time constants, 84 +/- 6 and 310 +/- 40 ms, at -100 mV, and was inhibited by 20 microM ZD7288. ISP and forskolin, both at 20 microM, enhanced I(h) by shifting the activation curve by 5.9 and 9.3 mV toward positive voltages, respectively. Under the current-clamp mode, ISP produced a depolarization of 7 +/- 3 mV in BCs and reduced their input resistance to 74 +/- 6%. ISP and a cAMP analogue, Rp-cAMP-S, increased the frequency of spontaneous spikes recorded from BCs using the cell-attached mode. The I(h) inhibitor ZD7288 decreased the BC spike frequency and abolished the ISP-induced increase in spike discharges. The results suggest that NE depolarizes the BCs through beta-adrenoceptor-mediated cAMP formation linking it to activation of I(h), which is, at least in part, involved in noradrenergic afferent-mediated facilitation of GABAergic synaptic activity at BC-PC connections in the rat cerebellum.Journal of Neurophysiology 11/2000; 84(4):2026-34. · 3.30 Impact Factor
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ABSTRACT: The expression of the voltage-gated K(+)-channel subunit Kv3.1b in the developing hippocampus was determined by immunoblot and immunohistochemical techniques. Kv3.1b protein was detected first at postnatal day (P) 8. The Kv3.1b-immunopositive cell number per tissue section reached a maximum at P14 and was maintained through P40. In contrast, the Kv3.1b protein content of isolated membrane vesicles in immunoblots progressively increased through P40, suggesting an increase in Kv3.1b content per cell throughout this time period. Kv3.1b protein was expressed selectively in the somata, proximal dendrites, and axons of cells lying within or near the pyramidal cell layer, consistent with their being GABAergic inhibitory interneurons. Kv3.1b was present in approximately 80% of parvalbumin-positive interneurons. The developmental onset of Kv3.1b and parvalbumin immunoreactivity was identical. In contrast, Kv3.1b was mostly absent from the subset of somatostatin-positive inhibitory interneurons. Electrophysiological recordings were made from stratum pyramidale interneurons in which morphology and Kv3.1b-positive immunoreactivity were confirmed post hoc. Outward currents had voltage-dependent and biophysical properties resembling those of channels formed by Kv3.1b. The current blocked by low concentrations of 4-aminopyridine (4-AP) showed marked inactivation, suggesting that Kv3.1b may coassemble with other members of the Kv3 subfamily. In current-clamp recordings, concentrations of 4-AP that blocked the current through Kv3.1b channels allowed us tentatively to assign a role to Kv3.1b-containing channels in action-potential repolarization. These data demonstrate that Kv3.1b is regulated developmentally in a specific subpopulation of hippocampal interneurons and that channels containing this subunit may be a major determinant in imparting "fast-spiking" characteristics to these and other cells throughout the central nervous system containing the Kv3.1b subunit.Journal of Neuroscience 02/1996; 16(2):506-18. · 6.91 Impact Factor
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ABSTRACT: AMPA receptors mediate fast synaptic transmission at excitatory synapses in the CNS and are crucial during neuronal development, synaptic plasticity and structural remodeling. AMPA receptors lacking GluR2 subunits are permeable to Ca(2+) and Zn(2+). Ca(2+) permeation through AMPA receptors is crucial in several forms of synaptic plasticity and cell death associated with neurological diseases and disorders. The subunit composition and Ca(2+) permeability of AMPA receptors are not static, but they are dynamically remodeled in a cell- and synapse-specific manner during development and in response to neuronal activity, sensory experience and neuronal insults. Exciting new research shows that these changes arise not only because of regulated expression of the AMPA receptor subunit GluR2, but also as a consequence of RNA editing, receptor trafficking and dendritic protein synthesis. This article reviews new insights into the role of Ca(2+)-permeable AMPA receptors in neuronal function and survival.Trends in Neurosciences 04/2007; 30(3):126-34. · 13.58 Impact Factor