title: Mice deficient in carbonic anhydrase type 8 exhibit motor dysfunctions and abnormal calcium dynamics in the somatic region of cerebellar granule cells.
abstract: The waddles (wdl) mouse is characterized by a namesake "side-to-side" waddling gait due to a homozygous mutation of the Car8 gene. This mutation results in non-functional copies of the protein carbonic anhydrase type 8. Rota-rod testing was conducted to characterize the wdl mutations' effect on motor output. Results indicated that younger homozygotes outperformed their older cohorts, an effect not seen in previous studies. Heterozygotes, which were thought to be free of motor impairment, displayed motor learning deficiencies when compared with wild type performance. Acute cerebellar slices were then utilized for fluorescent calcium imaging experiments, which revealed significant alterations in cerebellar granule cell somatic calcium signaling when exposed to glutamate. The contribution of GABAergic signaling to these alterations was also verified using bath application of bicuculline. Changes in somatic calcium signals were found to be applicable to an in vivo scenario by comparing group responses to electrical stimulation of afferent mossy fiber projections. Finally, intracellular calcium store function was also found to be altered by the wdl mutation when slices were treated with thapsigargin. These findings, taken together with previous work on the wdl mouse, indicate a widespread disruption in cerebellar circuitry hampering proper neuronal communication.
authors.affiliation: School of Pharmacy, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Lamont
authors.affiliation: School of Pharmacy, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada; Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada. Electronic address: jweber@mun.ca.
authors.forename: John T
authors.initials: JT
authors.lastname: Weber
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000172:deficiency* / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002491:Central Nervous System Agents / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology*; D015331:Cohort Studies; D004558:Electric Stimulation; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D007858:Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000502:physiology; D009069:Movement Disorders / Q000201:enzymology*; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D045442:Rotarod Performance Test; D012717:Sesquiterpenes / Q000494:pharmacology; D009435:Synaptic Transmission / Q000502:physiology; D046509:Tissue Culture Techniques; D002256:Carbonic Anhydrases
chemical_list: D001640:Bicuculline; D014408:Biomarkers, Tumor; D002118:Calcium; D002491:Central Nervous System Agents; D058787:GABA-A Receptor Antagonists; D018698:Glutamic Acid; D007783:Lactones; D009419:Nerve Tissue Proteins; D012717:Sesquiterpenes; C512821:Car8 protein, mouse; D002256:Carbonic Anhydrases; C046319:thapsigargicin
keywords: Ataxia; CAR8; Calcium signaling; Cerebellum; Granule cell; Waddles mouse