Neuroinflammation alters voltage-dependent conductance in striatal astrocytes

Karpuk, Nikolay; Burkovetskaya, Maria; Kielian, Tammy

doi:10.1152/jn.01182.2011

Cited by 10 publications

(8 citation statements)

References 32 publications

(60 reference statements)

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“…These results largely suggest that deep GM areas are more sensitive to Wallerian degeneration, either retrograde or anterograde. Our results agree with other findings showing the following: 1) Striatal regions are susceptible to damage from inflammation arising in other areas 32 , 33 ; 2) atrophy in the putamen, caudate, and thalamus is related to whole-brain T1 and T2 lesions in MS 34 ; 3) thalamic atrophy can be explained in part by lesion volume and mean diffusivity in WM tracts connecting to the thalamus 35 ; and 4) atrophy in deep GM regions of the caudate and pulvinar are related to ipsilateral WM lesion probability maps in highly connected regions. 36 In this cohort, overall observed atrophy was small (no regions showed significant group-wise atrophy after multiple-comparison corrections); however, regions with the most atrophy were the thalamus and other subcortical areas.…”

Section: Discussionsupporting

confidence: 93%

Modeling the Relationship among Gray Matter Atrophy, Abnormalities in Connecting White Matter, and Cognitive Performance in Early Multiple Sclerosis

Kuceyeski

Vargas²,

Dayan³

et al. 2014

AJNR Am J Neuroradiol

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Background and PurposeQuantitative assessment of clinical and pathologic consequences of white matter abnormalities in multiple sclerosis is critical in understanding the pathways of disease. This study aimed to test whether gray matter atrophy was related to abnormalities in connecting white matter and to identify patterns of imaging biomarker abnormalities that were related to patient processing speed.Materials and MethodsImage data and Symbol Digit Modalities Test scores were collected from a cohort of patients with early multiple sclerosis. The Network Modification Tool was used to estimate connectivity irregularities by projecting white matter abnormalities onto connecting gray matter regions. Partial least-squares regression quantified the relationship between imaging biomarkers and processing speed as measured by the Symbol Digit Modalities Test.ResultsAtrophy in deep gray matter structures of the thalami and putamen had moderate and significant correlations with abnormalities in connecting white matter (r = 0.39–0.41, P < .05 corrected). The 2 models of processing speed, 1 for each of the WM imaging biomarkers, had goodness-of-fit (R2) values of 0.42 and 0.30. A measure of the impact of white matter lesions on the connectivity of occipital and parietal areas had significant nonzero regression coefficients.ConclusionsWe concluded that deep gray matter regions may be susceptible to inflammation and/or demyelination in white matter, possibly having a higher sensitivity to remote degeneration, and that lesions affecting visual processing pathways were related to processing speed. The Network Modification Tool may be used to quantify the impact of early white matter abnormalities on both connecting gray matter structures and processing speed.

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Section: Discussionsupporting

confidence: 93%

Modeling the Relationship among Gray Matter Atrophy, Abnormalities in Connecting White Matter, and Cognitive Performance in Early Multiple Sclerosis

Kuceyeski

Vargas²,

Dayan³

et al. 2014

AJNR Am J Neuroradiol

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“…In agreement, whole cell patch clamp of S. aureus infected astrocytes have increased membrane capacitance (Karpuk et al, 2012). Therefore, localized acute neuroinflammation may have long term effects upon myelination by downregulating Cxs essential for maintaining oligodendrocyte integrity.…”

Section: Expression and Gjc In Parenchymal Cells Are Down Regulatesupporting

confidence: 56%

Regulation of gap junction channels by infectious agents and inflammation in the CNS

Castellano

Eugenín

2014

Front. Cell. Neurosci.

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Gap junctions (GJs) are conglomerates of intercellular channels that connect the cytoplasm of two or more cells, and facilitate the transfer of ions and small molecules, including second messengers, resulting in metabolic and electrical coordination. In general, loss of gap junctional communication (GJC) has been associated with cellular damage and inflammation resulting in compromise of physiological functions. Recently, it has become evident that GJ channels also play a critical role in the pathogenesis of infectious diseases and associated inflammation. Several pathogens use the transfer of intracellular signals through GJ channels to spread infection and toxic signals that amplify inflammation to neighboring cells. Thus, identification of the mechanisms by which several infectious agents alter GJC could result in new potential therapeutic approaches to reduce inflammation and their pathogenesis.

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“…Electrophysiological recordings of astrocytes were performed in the S1C and HPC of acute brain slices from CLN3 Δex7/8 and WT mice (n = 29/group) as previously described [93] . Acute brain slices were incubated with SR101 to facilitate astrocyte identification.…”

Section: Methodsmentioning

confidence: 99%

Evidence for Aberrant Astrocyte Hemichannel Activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL)

et al. 2014

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Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3 that leads to vision loss, progressive cognitive and motor decline, and premature death. Morphological evidence of astrocyte activation occurs early in the disease process and coincides with regions where neuronal loss eventually ensues. However, the consequences of CLN3 mutation on astrocyte function remain relatively ill-defined. Astrocytes play a critical role in CNS homeostasis, in part, by their ability to regulate the extracellular milieu via the formation of extensive syncytial networks coupled by gap junction (GJ) channels. In contrast, unopposed hemichannels (HCs) have been implicated in CNS pathology by allowing the non-discriminant passage of molecules between the intracellular and extracellular milieus. Here we examined acute brain slices from CLN3 mutant mice (CLN3Δex7/8) to determine whether CLN3 loss alters the balance of GJ and HC activity. CLN3Δex7/8 mice displayed transient increases in astrocyte HC opening at postnatal day 30 in numerous brain regions, compared to wild type (WT) animals; however, HC activity steadily decreased at postnatal days 60 and 90 in CLN3Δex7/8 astrocytes to reach levels lower than WT cells. This suggested a progressive decline in astrocyte function, which was supported by significant reductions in glutamine synthetase, GLAST, and connexin expression in CLN3Δex7/8 mice compared to WT animals. Based on the early increase in astrocyte HC activity, CLN3Δex7/8 mice were treated with the novel carbenoxolone derivative INI-0602 to inhibit HCs. Administration of INI-0602 for a one month period significantly reduced lysosomal ceroid inclusions in the brains of CLN3Δex7/8 mice compared to WT animals, which coincided with significant increases in astrocyte GJ communication and normalization of astrocyte resting membrane potential to WT levels. Collectively, these findings suggest that alterations in astrocyte communication may impact the progression of JNCL and could offer a potential therapeutic target.

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Neuroinflammation alters voltage-dependent conductance in striatal astrocytes

Cited by 10 publications

References 32 publications

Modeling the Relationship among Gray Matter Atrophy, Abnormalities in Connecting White Matter, and Cognitive Performance in Early Multiple Sclerosis

Modeling the Relationship among Gray Matter Atrophy, Abnormalities in Connecting White Matter, and Cognitive Performance in Early Multiple Sclerosis

Regulation of gap junction channels by infectious agents and inflammation in the CNS

Evidence for Aberrant Astrocyte Hemichannel Activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL)

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