Involvement of Kv1 Potassium Channels in Spreading Acidification and Depression in the Cerebellar Cortex

2005 ◽  
Vol 94 (2) ◽  
pp. 1287-1298 ◽  
Author(s):  
Gang Chen ◽  
Wangcai Gao ◽  
Kenneth C. Reinert ◽  
Laurentiu S. Popa ◽  
Claudia M. Hendrix ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Cerebellar Cortex ◽  
Molecular Layer ◽  
Neutral Red ◽  
Parallel Fiber ◽  
Null Mouse ◽  
Gabaergic Neurotransmission ◽  
Multiple Cycles

Spreading acidification and depression (SAD) is a form of propagated activity in the cerebellar cortex characterized by acidification and a transient depression in excitability. This study investigated the role of Kv1 potassium channels in SAD using neutral red, flavoprotein autofluorescence, and voltage-sensitive dye optical imaging in the mouse cerebellar cortex, in vivo. The probability of evoking SAD was greatly increased by blocking Kv1.1 as well as Kv1.2 potassium channels by their specific blockers dendrotoxin K (DTX-K) and tityustoxin (TsTX), respectively. DTX-K not only greatly lowered the threshold for evoking SAD but also resulted in multiple cycles of spread and spontaneous SAD. The occurrence of spontaneous SAD originating from spontaneous parallel fiber-like beams of activity suggests that blocking Kv1 channels increased parallel fiber excitability. This was confirmed by the generation of parallel fiber-like beams with the microinjection of glutamate into the upper molecular layer in the presence of DTX-K. The dramatic effects of DTX-K suggest a possible connection between SAD and episodic ataxia type 1 (EA1), a Kv1.1 potassium channelopathy. The threshold for evoking SAD was significantly lowered in the Kv1.1 heterozygous knockout mouse compared with wild-type littermates. Carbamazepine and acetazolamide, both effective in the treatment of EA1, significantly decreased the likelihood of evoking SAD. Blocking GABAergic neurotransmission did not alter the effectiveness of DTX-K. The cyclin D2 null mouse, which lacks cerebellar stellate cells, also exhibited SAD. Therefore blocking Kv1 potassium channels establishes the conditions needed to generate SAD. Furthermore, the results are consistent with the hypothesis that SAD may underlie the transient attacks of ataxia characterizing EA1.

scholarly journals Integrative Versus Delay Line Characteristics of Cerebellar Cortex

1976 ◽  
Vol 3 (2) ◽  
pp. 85-97 ◽  
Author(s):  
W.A. MacKay ◽  
J.T. Murphy
Keyword(s):  
Cerebellar Cortex ◽  
Cell Activation ◽  
Delay Line ◽  
Granule Cells ◽  
Molecular Layer ◽  
Parallel Fiber ◽  
Response Latencies ◽  
Integrator Model ◽  
P Cells

SUMMARY:In order to determine which of two general models (“tapped delay line” or “integrator”) provides a more accurate description of mammalian Purkinje cell (P-cell) activation by natural stimulation, the spatial and temporal characteristics of a population of neurons in cerebellar cortex responsive to small controlled stretches of forelimb muscles were examined in awake, locally anesthetized cats. Stretch of a single wrist muscle excited P-cells over a distance of about 1 mm in the long axis of a folium, a span which is at most half the length of parallel fibers. Both granule cells and molecular layer interneurons were excited over a wider zone than P-cells.Furthermore, P-cells across a response zone all fired on the average at the same time, as determined by computing peristimulus cross-interval histograms from pairs of simultaneously recorded neurons. Consistent delays could only be demonstrated in the minimal response latencies as measured from peristimulus time histograms. These delays, however, were longer than could be ascribed to parallel fiber conduction velocity.No evidence, therefore, was found in cat cerebellum to support the “tapped delay line” model, which postulates the successive activation of P-cells as an excitatory volley travels along a parallel fiber beam. Instead, an integrative mode of operation seems to predominate: a relatively wide substratum of activated granule cells simultaneously activates a narrower focus of P-cells centrally situated with respect to the granule cell population. The role of inhibitory interneurons in promoting the “integrator” model is discussed.

Feedforward Inhibition Controls the Spread of Granule Cell–Induced Purkinje Cell Activity in the Cerebellar Cortex

2007 ◽  
Vol 97 (1) ◽  
pp. 248-263 ◽  
Author(s):  
Fidel Santamaria ◽  
Patrick G. Tripp ◽  
James M. Bower
Keyword(s):  
Cerebellar Cortex ◽  
Granule Cells ◽  
Functional Organization ◽  
Cerebellar Granule Cells ◽  
Molecular Layer ◽  
Cell Activity ◽  
Excitatory Input ◽  
Cortical Inhibition ◽  
Before And After

Synapses associated with the parallel fiber (pf) axons of cerebellar granule cells constitute the largest excitatory input onto Purkinje cells (PCs). Although most theories of cerebellar function assume these synapses produce an excitatory sequential “beamlike” activation of PCs, numerous physiological studies have failed to find such beams. Using a computer model of the cerebellar cortex we predicted that the lack of PCs beams is explained by the concomitant pf activation of feedforward molecular layer inhibition. This prediction was tested, in vivo, by recording PCs sharing a common set of pfs before and after pharmacologically blocking inhibitory inputs. As predicted by the model, pf-induced beams of excitatory PC responses were seen only when inhibition was blocked. Blocking inhibition did not have a significant effect in the excitability of the cerebellar cortex. We conclude that pfs work in concert with feedforward cortical inhibition to regulate the excitability of the PC dendrite without directly influencing PC spiking output. This conclusion requires a significant reassessment of classical interpretations of the functional organization of the cerebellar cortex.

scholarly journals Loss of keratin 6 (K6) proteins reveals a function for intermediate filaments during wound repair

2003 ◽  
Vol 163 (2) ◽  
pp. 327-337 ◽  
Author(s):  
Pauline Wong ◽  
Pierre A. Coulombe
Keyword(s):  
Gene Expression ◽  
Wound Repair ◽  
Tissue Injury ◽  
Blood Clot ◽  
Explant Culture ◽  
Null Mouse ◽  
Actin Organization ◽  
Mammalian Tissues

The ability to heal wounds is vital to all organisms. In mammalian tissues, alterations in intermediate filament (IF) gene expression represent an early reaction of cells surviving injury. We investigated the role of keratin IFs during the epithelialization of skin wounds using a keratin 6α and 6β (K6α/K6β)-null mouse model. In skin explant culture, null keratinocytes exhibit an enhanced epithelialization potential due to increased migration. The extent of the phenotype is strain dependent, and is accompanied by alterations in keratin IF and F-actin organization. However, in wounded skin in vivo, null keratinocytes rupture as they attempt to migrate under the blood clot. Fragility of the K6α/K6β-null epidermis is confirmed when applying trauma to chemically treated skin. We propose that the alterations in IF gene expression after tissue injury foster a compromise between the need to display the cellular pliability necessary for timely migration and the requirement for resilience sufficient to withstand the rigors of a wound site.

In vivo location and mechanism of EDHF-mediated vasodilation in canine coronary microcirculation

1999 ◽  
Vol 277 (3) ◽  
pp. H1252-H1259 ◽  
Author(s):  
Yasuhiro Nishikawa ◽  
David W. Stepp ◽  
William M. Chilian
Keyword(s):  
Nitric Oxide ◽  
Potassium Channels ◽  
Potassium Channel ◽  
Direct Evidence ◽  
Coronary Microcirculation ◽  
Combined Administration ◽  
Cytochrome P 450 ◽  
Coronary Arterioles

Responses of epicardial coronary arterioles to ACh were measured using stroboscopic fluorescence microangiography in dogs ( n = 38). ACh (0.1 and 0.5 μg ⋅ kg−1 ⋅ min−1ic) dilated small (<100 μm, 11 ± 2 and 19 ± 2%, respectively) and large (>100 μm, 6 ± 3 and 13 ± 3%, respectively) arterioles at baseline. Combined administration of N ω-monomethyl-l-arginine (l-NMMA; 1.0 μmol/min ic) and indomethacin (10 mg/kg iv) eliminated ACh-induced dilation in large coronary arterioles but only partially attenuated that in small arterioles. Suffusion of a buffer containing 60 mM KCl (high KCl) completely abolished cromakalim-induced dilation in arterioles and in combination with l-NMMA plus indomethacin completely blocked ACh-induced dilation in small arterioles. This indicated that the vasodilation to ACh that persists in small arterioles after administration of l-NMMA and indomethacin is mediated via a hyperpolarizing factor. The ACh-induced vasodilation remaining after l-NMMA and indomethacin was completely blocked by the large-conductance potassium-channel antagonist iberiotoxin or by epicardial suffusion of miconazole or metyrapone, inhibitors of cytochrome P-450 enzymes. These observations are consistent with the view that endothelium-derived hyperpolarizing factor (EDHF) is a product of cytochrome P-450 enzymes and produces vasodilation by the opening of large-conductance potassium channels. We conclude that ACh-induced dilation in large coronary arterioles is mediated mainly by nitric oxide (NO), whereas, in small arterioles both NO and EDHF mediate dilation to ACh. These data provide the first direct evidence for an in vivo role of EDHF in small coronary arterioles.

The role of ATP-sensitive potassium channels in striatal dopamine release: An in vivo microdialysis study

1995 ◽  
Vol 52 (4) ◽  
pp. 831-835 ◽  
Author(s):  
Takahiko Tanaka ◽  
Masami Yoshida ◽  
Hideyasu Yokoo ◽  
Katsuhiro Mizoguchi ◽  
Masatoshi Tanaka
Keyword(s):  
Potassium Channels ◽  
Dopamine Release ◽  
In Vivo Microdialysis ◽  
Striatal Dopamine ◽  
Striatal Dopamine Release ◽  
Microdialysis Study

Role of ATP-sensitive potassium channels in the basilar artery

1993 ◽  
Vol 264 (1) ◽  
pp. H8-H13 ◽  
Author(s):  
F. M. Faraci ◽  
D. D. Heistad
Keyword(s):  
Potassium Channels ◽  
Basilar Artery ◽  
Cranial Window ◽  
Basal Tone ◽  
Dependent Inhibition ◽  
Baseline Diameter ◽  
Direct Activator ◽  
Sustained Increase

This study examined the hypothesis that activation of ATP-sensitive potassium channels produces vasodilation and contributes to dilator responses of the basilar artery to acetylcholine in vivo. Diameter of the basilar artery (baseline diam = 245 +/- 14 microns, means +/- SE) was measured through a cranial window in anesthetized rats. RP52891 (1 microM), a direct activator of ATP-sensitive potassium channels, increased the diameter of the basilar artery by 33 +/- 5%. Glibenclamide (1 microM), an inhibitor of ATP-sensitive potassium channels, did not alter baseline diameter but abolished responses of the basilar artery to RP52891. Topical application of acetylcholine (10 microM) for 3 min produced peak dilatation of 33 +/- 6% at 30 s and produced a sustained increase in diameter of 17 +/- 4%. Glibenclamide did not inhibit dilator responses of the basilar artery to acetylcholine. Nitro-L-arginine methyl ester (10 and 100 microM), which inhibits synthesis of endothelium-derived relaxing factor (EDRF), produced concentration-dependent inhibition of dilatation of the basilar artery in response to acetylcholine. Thus ATP-sensitive potassium channels are functional but do not appear to influence basal tone of the basilar artery. Dilator responses of the basilar artery to acetylcholine are dependent on formation of EDRF but not dependent on activity of glibenclamide-sensitive potassium channels.

Glutamate microinjections in cerebellar cortex reproduce cerebrovascular effects of parallel fiber stimulation

1996 ◽  
Vol 271 (6) ◽  
pp. R1568-R1575 ◽  
Author(s):  
G. Yang ◽  
C. Iadecola
Keyword(s):  
Glutamate Receptors ◽  
Cerebellar Cortex ◽  
Glutamate Release ◽  
Molecular Layer ◽  
Parallel Fiber ◽  
Synaptic Activity ◽  
No Production ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Fiber Stimulation

Electrical stimulation of cerebellar parallel fibers releases glutamate and increases local blood flow (BFcrb), an effect in part mediated by glutamate-induced nitric oxide (NO) production. We studied whether local microinjection of glutamate into the cerebellar cortex would produce increases in BFcrb comparable to those elicited by parallel fiber stimulation. In halothane-anesthetized rats equipped with a cranial window, glutamate was microinjected into the cerebellar molecular layer, and BFcrb was monitored by laser-Doppler flowmetry. Glutamate microinjections increased BFcrb dose dependently (2-200 pmol in 200 nl) (n = 9) and by 55 +/- 6% at 200 pmol (mean +/- SE). The magnitude and temporal profile of the increases in BFcrb compared favorably with the increase in flow produced by parallel fiber stimulation. The glutamate-induced BFcrb increase was attenuated by superfusion with the Na2+ channel blocker tetrodotoxin (10 microM; -50 +/- 10%; n = 5; P < 0.05; t-test) or by blocking synaptic activity by treatment of the cerebellar cortex with Ringer containing 20 mM Mg2+ and 0 mM Ca2+ (-80 +/- 4%; n = 6; P < 0.05). The glutamate-receptor antagonist kynurenate (10 mM) attenuated the increase in BFcrb by 59 +/- 6% (P < 0.05; n = 5). The relatively selective inhibitor of neuronal NO synthase 7-nitroindazole (100 mg/kg ip) reduced the flow response evoked by microinjection of glutamate (-46 +/- 7%; n = 5; P < 0.05) but not acetylcholine (10 microM; P > 0.05; n = 6). We conclude that glutamate microinjections increase local BFcrb via activation of glutamate receptors. The glutamate-induced vasodilation is mediated, in part, by neurally derived NO. The striking similarities between the vascular responses evoked by parallel fiber stimulation and that produced by microinjection of glutamate support the hypothesis that the increase in BFcrb produced by parallel fiber stimulation is mediated by glutamate release and activation of glutamate receptors. The data also strengthen the hypothesis that glutamate and NO are important mediators in the mechanisms linking synaptic activity to BFcrb in cerebellar cortex.

scholarly journals DR5 Knockout Mice Are Compromised in Radiation-Induced Apoptosis

2005 ◽  
Vol 25 (5) ◽  
pp. 2000-2013 ◽  
Author(s):  
Niklas Finnberg ◽  
Joshua J. Gruber ◽  
Peiwen Fei ◽  
Dorothea Rudolph ◽  
Anka Bric ◽  
...  
Keyword(s):  
Cell Death ◽  
Null Mouse ◽  
Organ Specific ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
The Brain ◽  
Necrosis Factor

ABSTRACT DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli.

scholarly journals The Anatomical Distribution of Mechanoreceptors in Mouse Hind Paw Skin and the Influence of Integrin α1β1 on Meissner-Like Corpuscle Density in the Footpads

2021 ◽  
Vol 15 ◽  
Author(s):  
Valerie Wai ◽  
Lauren Roberts ◽  
Jana Michaud ◽  
Leah R. Bent ◽  
Andrea L. Clark
Keyword(s):  
Sensory Feedback ◽  
Receptive Fields ◽  
Glabrous Skin ◽  
Null Mouse ◽  
Merkel Cells ◽  
Wild Type ◽  
Anatomical Distribution ◽  
Footfall Patterns

Afferent neurons and their mechanoreceptors provide critical sensory feedback for gait. The anatomical distribution and density of afferents and mechanoreceptors influence sensory feedback, as does mechanoreceptor function. Electrophysiological studies of hind paw skin reveal the different types of afferent responses and their receptive fields, however, the anatomical distribution of mechanoreceptor endings is unknown. Also, the role of integrin α1β1 in mechanoreceptor function is unclear, though it is expressed by keratinocytes in the stratum basale where it is likely involved in a variety of mechanotransduction pathways and ion channel functionalities. For example, it has been shown that integrin α1β1 is necessary for the function of TRPV4 that is highly expressed by afferent units. The purpose of this study, therefore, was to determine and compare the distribution of mechanoreceptors across the hind paw skin and the footfall patterns of itga1-null and wild type mice. The itga1-null mouse is lacking the integrin α1 subunit, which binds exclusively to the β1 subunit, thus rendering integrin α1β1 nonfunctional while leaving the numerous other pairings of the β1 subunit undisturbed. Intact hind paws were processed, serially sectioned, and stained to visualize mechanoreceptors. Footfall patterns were analyzed as a first step in correlating mechanoreceptor distribution and functionality. Merkel cells and Meissner-like corpuscles were present, however, Ruffini endings and Pacinian corpuscles were not observed. Meissner-like corpuscles were located exclusively in the glabrous skin of the footpads and digit tips, however, Merkel cells were found throughout hairy and glabrous skin. The increased density of Merkel cells and Meissner-like corpuscles in footpads 1 and 3 and Meissner-like corpuscles in footpad 4 suggests their role in anteroposterior balance, while Meissner-like corpuscle concentrations in digits 2 and 5 support their role in mediolateral balance. Finally, a larger density of Meissner-like corpuscles in footpads 3 and 4 in male itga1-null mice compared to wild type controls paves the way for future site-specific single fiber in vivo recordings to provide insight into the role of integrin α1β1 in tactile mechanotransduction.

Sign in / Sign up

Export Citation Format

Share Document