Age-dependent emergence of neurophysiological and behavioral abnormalities in progranulin-deficient mice

Loss-of-function mutations in the progranulin gene cause frontotemporal dementia, a genetic, heterogeneous neurodegenerative disorder. Progranulin deficiency leads to extensive neuronal loss in the frontal and temporal lobes, altered synaptic connectivity, and behavioral alterations. The chronologic...

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Published inAlzheimer's research & therapy Vol. 11; no. 1; p. 88
Main Authors Nagy, Dávid, Martens, Lauren Herl, Leventhal, Liza, Chen, Angela, Kelley, Craig, Stoiljkovic, Milan, Hajós, Mihály
Format Journal Article
LanguageEnglish
Published England BioMed Central Ltd 22.10.2019
BioMed Central
BMC
Subjects
Analysis
Brain
Causes of
Dementia
Electrophysiology
Frontotemporal dementia
Genes
Genetic aspects
Nervous system diseases
Neurodegenerative diseases
Neurons
Neurophysiology
Phenotypes
Prefrontal cortex
Progranulin
Reward-seeking/processing
United States
Electrophysiology
Reward-seeking/processing
Progranulin
Prefrontal cortex
Frontotemporal dementia
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Summary:Loss-of-function mutations in the progranulin gene cause frontotemporal dementia, a genetic, heterogeneous neurodegenerative disorder. Progranulin deficiency leads to extensive neuronal loss in the frontal and temporal lobes, altered synaptic connectivity, and behavioral alterations. The chronological emergence of neurophysiological and behavioral phenotypes of Grn heterozygous and homozygous mice in the dorsomedial thalamic-medial prefrontal cortical pathway were evaluated by in vivo electrophysiology and reward-seeking/processing behavior, tested between ages 3 and 12.5 months. Electrophysiological recordings identified a clear age-dependent deficit in the thalamocortical circuit. Both heterozygous and homozygous mice exhibited impaired input-output relationships and paired-pulse depression, but evoked response latencies were only prolonged in heterozygotes. Furthermore, we demonstrate firstly an abnormal reward-seeking/processing behavior in the homozygous mice which correlates with previously reported neuroinflammation. Our findings indicate that murine progranulin deficiency causes age-dependent neurophysiological and behavioral abnormalities thereby indicating their validity in modeling aspects of human frontotemporal dementia.
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ISSN:1758-9193
1758-9193
DOI:10.1186/s13195-019-0540-x