TY - JOUR
T1 - Cerebellar vascular and synaptic responses in normal mice and in transgenics with Purkinje cell dysfunction
AU - Yang, Guang
AU - Feddersen, Rod M.
AU - Zhang, Fangyi
AU - Clark, H. Brent
AU - Beitz, Al J
AU - Iadecola, Costantino
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 1998/2
Y1 - 1998/2
N2 - We used transgenic mice with Purkinje cell dysfunction (PO3 line) to study the role of these neurons in the increase in cerebellar blood flow (BF(crb)) produced by stimulation of the cerebellar parallel fibers (PF). Mice (age 8-10 wk) were anesthetized (halothane) and artificially ventilated. Arterial pressure and end-tidal CO2 were monitored continuously. Arterial blood gases were measured. The PF were stimulated electrically (100 μA, 30 Hz; 40 s), and the increases in BF(crb) were monitored by a laser-Doppler flow probe. First, we characterized the increases in BF(crb) and the field potentials produced by PF stimulation in normal mice. PF stimulation evoked the typical field potentials and increased BF(crb) by 60 ± 4% (100 μA, 30 Hz; n = 10). The increases in BF(crb) were attenuated by the broad-spectrum glutamate receptor antagonist kynurenate (-84 ± 3%; P < 0.05 analysis of variance; n = 5), by the DL-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl- benzo(f)quinoxaline (-62 ± 6%; P < 0.05; n = 5), and by the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine (-46 ± 7%; P < 0.05; n = 5). In PO3 transgenic mice, the increases in BF(crb) produced by PF stimulation were reduced (P < 0.001) at every stimulus intensity and frequency tested (residual increase at 100 μA, 30 Hz: 19 ± 2%; n = 6). The field potentials evoked by PF stimulation also were abnormal in that they lacked the late negative wave (n = 6), a finding consistent with lack of depolarization of Purkinje cells. The residual flow response in the transgenics was abolished by N(ω)-nitro-L-arginine (n = 5; P > 0.05). Ultrastructural studies showed that the density of PF-Purkinje cell synapses is reduced in PO3 mice, whereas the morphology of molecular layer interneurons (stellate cells) is normal. The findings suggest that Purkinje cells are responsible for a sizable component of the flow response whereas molecular layer interneurons mediate the remainder of the response. The study provides evidence that mouse mutants with spontaneous or genetically engineered cerebellar abnormalities could be useful to study the cellular and molecular correlates of functional hyperemia in the central nervous system.
AB - We used transgenic mice with Purkinje cell dysfunction (PO3 line) to study the role of these neurons in the increase in cerebellar blood flow (BF(crb)) produced by stimulation of the cerebellar parallel fibers (PF). Mice (age 8-10 wk) were anesthetized (halothane) and artificially ventilated. Arterial pressure and end-tidal CO2 were monitored continuously. Arterial blood gases were measured. The PF were stimulated electrically (100 μA, 30 Hz; 40 s), and the increases in BF(crb) were monitored by a laser-Doppler flow probe. First, we characterized the increases in BF(crb) and the field potentials produced by PF stimulation in normal mice. PF stimulation evoked the typical field potentials and increased BF(crb) by 60 ± 4% (100 μA, 30 Hz; n = 10). The increases in BF(crb) were attenuated by the broad-spectrum glutamate receptor antagonist kynurenate (-84 ± 3%; P < 0.05 analysis of variance; n = 5), by the DL-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl- benzo(f)quinoxaline (-62 ± 6%; P < 0.05; n = 5), and by the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine (-46 ± 7%; P < 0.05; n = 5). In PO3 transgenic mice, the increases in BF(crb) produced by PF stimulation were reduced (P < 0.001) at every stimulus intensity and frequency tested (residual increase at 100 μA, 30 Hz: 19 ± 2%; n = 6). The field potentials evoked by PF stimulation also were abnormal in that they lacked the late negative wave (n = 6), a finding consistent with lack of depolarization of Purkinje cells. The residual flow response in the transgenics was abolished by N(ω)-nitro-L-arginine (n = 5; P > 0.05). Ultrastructural studies showed that the density of PF-Purkinje cell synapses is reduced in PO3 mice, whereas the morphology of molecular layer interneurons (stellate cells) is normal. The findings suggest that Purkinje cells are responsible for a sizable component of the flow response whereas molecular layer interneurons mediate the remainder of the response. The study provides evidence that mouse mutants with spontaneous or genetically engineered cerebellar abnormalities could be useful to study the cellular and molecular correlates of functional hyperemia in the central nervous system.
KW - Cerebellum
KW - Cerebral circulation
KW - Glutamate
KW - Laser-Doppler flowmetry
KW - Vasodilation
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U2 - 10.1152/ajpregu.1998.274.2.r529
DO - 10.1152/ajpregu.1998.274.2.r529
M3 - Article
C2 - 9486314
AN - SCOPUS:0031887524
SN - 0363-6119
VL - 274
SP - R529-R540
JO - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
JF - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
IS - 2 43-2
ER -