Dataset Information

Chronic Microglial Activation in the GFAP-IL6 Mouse Contributes to Age-Dependent Cerebellar Volume Loss and Impairment in Motor Function.

ABSTRACT: Chronic microglial activation is a prominent feature of many chronic neurodegenerative diseases, including Parkinson's and Alzheimer's disease. To investigate the effects of chronic microglial activation on cerebellar structure and motor function throughout the lifespan, the transgenic GFAP-IL6 mouse model was used. The aim of the study was to examine inflammatory markers and neuronal degeneration while simultaneously characterizing the motor performance of GFAP-IL6 mice at 3, 6, 14, and 24 months of age in comparison to WT (C57BL/6) mice. In respect to markers of neuroinflammation in the cerebellum, increased numbers of Iba1+ microglia were observed as early as at 3 months of age. In addition, TNF-? levels proved to be significantly higher in the GFAP-IL6 compared to WT mice at all time points. A difference in cerebellar volume between the GFAP-IL6 and WT mice was observed later in life, starting at 6 months and increasing to a loss of about 50% in aged (24 months old) GFAP-IL6 mice. Synaptic deficits were also assessed by using pre- (synaptophysin) and post-synaptic (PSD95) markers. While synaptophysin levels remained unchanged, PSD95 levels decreased in the aging GFAP-IL6 mice compared to their WT littermates from 14 months onward. To assess the effect of microglia activation and neurodegeneration on behavior, a variety of motor function tests, semi-quantitative cerebellar ataxia score, accelerod, beam walking, and open field tests were performed. An age-dependent difference between the genotypes was observed in many of the motor function tests. For example, reduced performance on the accelerod and higher ataxia scores were observed at 6 months of age, followed by the beam walking test showing differences at 14 months of age. In summary, this study constitutes a comprehensive, age-dependent examination of inflammatory, synaptic and neurodegenerative changes in the brains of GFAP-IL6 mice leading to a deterioration in motor performance. The results also indicate that early chronic microglia activation in the GFAP-IL6 mouse leads to observable cerebellar volume loss and motor deficits later in life.

SUBMITTER: Gyengesi E

PROVIDER: S-EPMC6456818 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Chronic Microglial Activation in the GFAP-IL6 Mouse Contributes to Age-Dependent Cerebellar Volume Loss and Impairment in Motor Function.

Gyengesi Erika E Rangel Alejandra A Ullah Faheem F Liang Huazheng H Niedermayer Garry G Asgarov Rustam R Venigalla Madhuri M Gunawardena Dhanushka D Karl Tim T Münch Gerald G

Frontiers in neuroscience 20190403

Chronic microglial activation is a prominent feature of many chronic neurodegenerative diseases, including Parkinson's and Alzheimer's disease. To investigate the effects of chronic microglial activation on cerebellar structure and motor function throughout the lifespan, the transgenic GFAP-IL6 mouse model was used. The aim of the study was to examine inflammatory markers and neuronal degeneration while simultaneously characterizing the motor performance of GFAP-IL6 mice at 3, 6, 14, and 24 mont ...[more]

PMID: 31001075

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Project description:Recently, we have identified two astrocytic subpopulations in the cortex of GFAP-EGFP mice, in which the astrocytes are visualized by the enhanced green-fluorescent protein (EGFP) under the control of the human glial fibrillary acidic protein (GFAP) promotor. These astrocytic subpopulations, termed high response- (HR-) and low response- (LR-) astrocytes, differed in the extent of their swelling during oxygen-glucose deprivation (OGD). In the present study we focused on identifying the ion channels or transporters that might underlie the different capabilities of these two astrocytic subpopulations to regulate their volume during OGD. Using three-dimensional confocal morphometry, which enables quantification of the total astrocytic volume, the effects of selected inhibitors of K? and Cl? channels/transporters or glutamate transporters on astrocyte volume changes were determined during 20 minute-OGD in situ. The inhibition of volume regulated anion channels (VRACs) and two-pore domain potassium channels (K(2P)) highlighted their distinct contributions to volume regulation in HR-/LR-astrocytes. While the inhibition of VRACs or K(2P) channels revealed their contribution to the swelling of HR-astrocytes, in LR-astrocytes they were both involved in anion/K? effluxes. Additionally, the inhibition of Na?-K?-Cl? co-transporters in HR-astrocytes led to a reduction of cell swelling, but it had no effect on LR-astrocyte volume. Moreover, employing real-time single-cell quantitative polymerase chain reaction (PCR), we characterized the expression profiles of EGFP-positive astrocytes with a focus on those ion channels and transporters participating in astrocyte swelling and volume regulation. The PCR data revealed the existence of two astrocytic subpopulations markedly differing in their gene expression levels for inwardly rectifying K? channels (Kir4.1), K(2P) channels (TREK-1 and TWIK-1) and Cl? channels (ClC2). Thus, we propose that the diverse volume changes displayed by cortical astrocytes during OGD mainly result from their distinct expression patterns of ClC2 and K(2P) channels.

Dataset Information

Chronic Microglial Activation in the GFAP-IL6 Mouse Contributes to Age-Dependent Cerebellar Volume Loss and Impairment in Motor Function.

Publications

Chronic Microglial Activation in the GFAP-IL6 Mouse Contributes to Age-Dependent Cerebellar Volume Loss and Impairment in Motor Function.

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