Dysfunctional Calcium and Glutamate Signaling in Striatal Astrocytes from Huntington's Disease Model Mice

Jiang, Ruotian; Díaz-Castro, Blanca; Looger, Loren L.; Khakh, Baljit S.

doi:10.1523/jneurosci.3693-15.2016

Cited by 187 publications

(178 citation statements)

References 65 publications

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“…Genetic restoration of Kir4.1 levels in striatal astrocytes returned extracellular K + and MSN excitability to normal, along with improvement of some motor functions in R6/2 mice (Tong et al, 2014). Recent work confirmed that the loss of astrocytic Kir4.1‐ and EAAT2‐mediated homeostatic functions in R6/2 mice compromises glutamate handling and Ca 2+ signaling, contributing to MSNs pathology in the striatum (Jiang, Diaz‐Castro, Looger, & Khakh, 2016). It follows, that the loss of astrocytic control over glutamate and potassium extracellular levels may contribute to pathology seen in HD and the proteins affected by HD in astrocytes, such as EAAT2 and Kir4.1 channels, might represent therapeutic targets in HD.…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 90%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 90%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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“…iGluSnFR also allows mesoscale "functional connectomic" mapping 6 and mechanistic studies of Huntington's disease 7 , synaptic spillover 8 , cortical spreading depression 9 and exocytotic vesicle fusion 10 . However, iGluSnFR is insufficient for some applications due to poor expression (in some preparations), and kinetics that do not match the time courses of some phenomena.…”

Section: Main Textmentioning

confidence: 99%

Stability, affinity and chromatic variants of the glutamate sensor iGluSnFR

Marvin

Scholl

Wilson

et al. 2017

Preprint

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Single-wavelength fluorescent reporters allow visualization of specific neurotransmitters with high spatial and temporal resolution. We report variants of the glutamate sensor iGluSnFR that are functionally brighter; can detect sub-micromolar to millimolar concentrations of glutamate; and have blue, green or yellow emission profiles. These variants allow in vivo imaging where original-iGluSnFR was too dim, reveal glutamate transients at individual spine heads, and permit kilohertz imaging with inexpensive, powerful fiber lasers. Main TextThe intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) 1 has become an invaluable tool for studying glutamate dynamics in diverse systems, including retina 2,3 , olfactory bulb 4 and visual cortex 5 . iGluSnFR also allows mesoscale "functional connectomic" mapping 6 and mechanistic studies of Huntington's disease 7 , synaptic spillover 8 , cortical spreading depression 9 and exocytotic vesicle fusion 10 . However, iGluSnFR is insufficient for some applications due to poor expression (in some preparations), and kinetics that do not match the time courses of some phenomena. Here we describe variants that are functionally brighter (due to increased membrane expression), have tighter or weaker affinity, and fluoresce blue, green, or yellow.Replacement of circularly permuted eGFP with circularly permuted "superfolder" GFP 11 (SFiGluSnFR) yielded 5-fold higher soluble-protein expression levels in bacteria (0.5 µmol/1L growth vs. 0.1 µmol/1L). Circular dichroism indicates an increase in melting temperature transition (T m ) of ~5˚C (Supp. Fig. S1). The 2-photon cross-section and excitation, emission, and absorption spectra of SF-iGluSnFR are similar to the original (Supp. Fig. S2a-d). Head-tohead comparison of SF-iGluSnFR with original-iGluSnFR in mouse somatosensory cortex shows substantially more robust expression by the former (Supp. Fig. S3a,b). Under typical imaging conditions (<20 mW, 130-nanosecond dwell time per pixel), SF-iGluSnFR is bright enough for repeated imaging, while original-iGluSnFR is too dim (Supp. Fig. S3c,d). While we observed a faster 2-photon in vivo photobleaching rate for SF-iGluSnFR in somatosensory cortex (Supp. Fig. S3e), partially-bleached SF-iGluSnFR was still brighter than iGluSnFR. Thus, SF-iGluSnFR will have superior expression in vivo, where the quantity of deliverable DNA can be limiting.While the affinity of membrane-displayed iGluSnFR (4 µM) is adequate for some in vivo applications, tighter variants are needed for circumstances of limiting glutamate concentrations, e.g. at sparsely-firing synapses. Additionally, measuring glutamate release events with raster scanning requires variants with slower off-rates so that the decay time from glutamate binding is long enough to be sufficiently sampled at the operating frame rate (typically <100 Hz). Replacement of eGFP with superfolder GFP increases the in vitro affinity of soluble SFiGluSnFR over original-iGluSnFR (40 µM vs. 80 µM, Supp. Fig. S4a). To further modulate affinity, w...

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“…Astrocyte Ca 2+ signals have thus recently been explored in a mouse model of HD[110]. Notably, at the ages tested, HD model mice did not display astrogliosis [109] and thus the underlying changes that occur are separable from those observed in AD model mice, which are strongly associated with astrogliosis [102].…”

Section: Introductionmentioning

confidence: 99%

Probing the Complexities of Astrocyte Calcium Signaling

Shigetomi

Patel

Khakh

2016

Trends in Cell Biology

220

199

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Astrocytes are abundant glial cells that tile the entire central nervous system and mediate well established functions for neurons, blood vessels and other glia. These ubiquitous cells display intracellular Ca2+ signals, which have been intensely studied for 25 years. Recently, the use of improved methods has unearthed the panoply of astrocyte Ca2+ signals and a variable landscape of basal Ca2+ levels. In vivo studies have started to reveal the settings under which astrocytes display behaviorally relevant Ca2+ signaling. Studies in mice have emphasized how astrocyte Ca2+ signaling is altered in distinct neurodegenerative diseases. Progress in the last few years, fueled by methodological advances, has thus reignited interest in astrocyte Ca2+ signaling for brain function and dysfunction.

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Dysfunctional Calcium and Glutamate Signaling in Striatal Astrocytes from Huntington's Disease Model Mice

Cited by 187 publications

References 65 publications

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Stability, affinity and chromatic variants of the glutamate sensor iGluSnFR

Probing the Complexities of Astrocyte Calcium Signaling

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