Reduction of K⁺Uptake in Glia Prevents Long-Term Depression Maintenance and Causes Epileptiform Activity

Abstract

Extracellular cesium causes synchronous, interictal-like bursting and prevents maintenance of long-term depression (LTD) in the CA1 hippocampal region. We have investigated the cellular mechanisms underlying cesium actions. Whole-cell recordings showed that brief (2 min) bath exposures to cesium caused pyramidal cell hyperpolarization associated with decreased membrane conductance attributable to blockade of an inward h-type current. After prolonged (Ͼ2 min) exposures, a late depolarizing response was observed; this effect was not associated with changes in cell membrane conductance. Recordings from interneurons revealed that I h is expressed in a subpopulation of cells and that cesium effects on interneurons expressing I h are comparable to those observed in pyramidal cells. Consistent with this effect, cesium decreased the early component of the IPSP recorded in pyramidal cells. Interneurons lacking I h were not affected by cesium but developed a depolarizing response when drug applications were paired to orthodromic stimulation. We concluded that cesium actions on LTD and cesium-induced epileptiform activity were not attributable exclusively to its direct effects on neurons. Recordings from hippocampal slice astrocytes revealed that cesium interfered with glial electrical responses during LTD induction. Cesium blocked glial inwardly rectifying potassium channels and increased the amplitude and duration of stimulation-evoked [K ϩ ] out increases. Thus, the effects of cesium on CA1 synchronization and synaptic plasticity appear to be mediated predominantly by blockade of glial voltage-dependent potassium uptake.

Heterogeneity of Astrocyte Resting Membrane Potentials and Intercellular Coupling Revealed by Whole-Cell and Gramicidin-Perforated Patch Recordings from Cultured Neocortical and Hippocampal Slice Astrocytes

“…Hippocampal slices were prepared from 18-to 25-d-old male Wistar rats (Janigro et al, 1997a). Briefly, halothaneanesthetized rats were decapitated, and the heads were kept in ice-cold, oxygenated-modified artificial CSF composed of (in mM): 120 NaCl, 3.1 KCl, 4 MgCl 2 , 1 CaCl 2 , 1.25 KH 2 PO 4 , 26 NaHC0 3 , and 10 dextrose.…”

“…The experiments performed to elucidate the electrical behavior of in situ glial cells were performed with either a wholecell patch or perforated patch technique (Janigro et al, 1997a) from visually identified cells in the stratum radiatum of the hippocampal CA1 and CA3 regions. Astrocytes were initially identified morphologically based on the characteristic size and shape of their soma; this identification was f urther confirmed by histochemical analysis on biocytin-filled cells (R. D'Ambrosio, G. M. McK hann II, and D. Janigro, unpublished results).…”

“…We routinely used K F to monitor patch-rupturing events. Accidental rupture of the seal was characterized by a large and sudden depolarization attributable to the blocking action of intracellular K F on potassium currents (Janigro et al, 1997a). Pipettes had a resistance of ϳ5 M⍀.…”

Ih Blockers Have a Potential of Antiepileptic Effects

“…Recently the h current (Ih) has been investigated (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), and the following characteristics of Ih were reported: (a) Ih is a voltage-gated nonselective cationic conductance activated by membrane hyperpolarization, not by depolarization (8,14); (b) Ih is blocked by cesium chloride (CsCl) or 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride (ZD7288) instead of tetrodotoxin (8,13,15); and (c) Ih channels occur in higher density in the apical dendrites than in the soma (8,14). In spite of many in vitro reports on Ih channels (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) as well as in vivo studies on the pacemaking function of Ih (25)(26)(27)(28), any contributions of Ih to epileptic activity are unknown in vivo, except for the one that showed the...…”

“…In spite of many in vitro reports on Ih channels (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) as well as in vivo studies on the pacemaking function of Ih (25)(26)(27)(28), any contributions of Ih to epileptic activity are unknown in vivo, except for the one that showed the long-lasting enhancement of the widely expressed intrinsic Ih that converts the potentiated synaptic inhibition to hyperexcitability in the hippocampus of rats that had febrile seizures (29).…”