Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target

Hiu, Takeshi; Farzampour, Zoya; Paz, Jeanne T.; Wang, Eric Hou Jen; Badgely, Corrine; Olson, Andrew; Micheva, Kristina D.; Wang, Gordon; Lemmens, Robin; Tran, Kevin V.; Nishiyama, Yasuhiro; Liang, Xin; Hamilton, Scott; O’Rourke, Nancy A.; Smith, Stephen J.; Huguenard, John R.; Bliss, Tonya; Steinberg, Gary K.

doi:10.1093/brain/awv360

Cited by 100 publications

(85 citation statements)

References 53 publications

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“…25 Furthermore, altered tonic and phasic GABA (gamma aminobutyric acid) (Cl − ) signaling has been reported to occur after stroke, and targeted treatments provide behavioral benefit. 26,27 Taken together, these findings indicate that ion homeostasis is impaired after nervous system injury with functional consequences, and therapies that normalize ion concentration or signaling, including rehabilitation, can be beneficial. However, it should be noted that beginning such treatments soon after stroke can be harmful (eg, increased lesion size).…”

Section: Discussionmentioning

confidence: 91%

Rehabilitation Augments Hematoma Clearance and Attenuates Oxidative Injury and Ion Dyshomeostasis After Brain Hemorrhage

Dietrich

Hackett

Caine

et al. 2017

Stroke

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Section: Discussionmentioning

confidence: 91%

Rehabilitation Augments Hematoma Clearance and Attenuates Oxidative Injury and Ion Dyshomeostasis After Brain Hemorrhage

Dietrich

Hackett

Caine

et al. 2017

Stroke

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“…Interestingly, while tonic GABA signaling is increased after stroke, phasic GABA signaling mediated via synaptic GABA-A receptors is decreased after stroke. Recently our group demonstrated that enhancing phasic GABA signaling promotes post-stroke recovery, further highlighting the importance of phasic GABA signaling in recovery [157]. The GABA-B receptor may also play an important role in stroke recovery, as these receptors are thought to mediate interhemispheric inhibition [158].…”

Section: Optogenetic Interrogation Of Post-stroke Remapping and Recoverymentioning

confidence: 97%

Optogenetic Approaches to Target Specific Neural Circuits in Post-stroke Recovery

2016

Self Cite

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Stroke is a leading cause of death and disability in the USA, yet treatment options are very limited. Functional recovery can occur after stroke and is attributed, in part, to rewiring of neural connections in areas adjacent to or remotely connected to the infarct. A better understanding of neural circuit rewiring is thus an important step toward developing future therapeutic strategies for stroke recovery. Because stroke disrupts functional connections in peri-infarct and remotely connected regions, it is important to investigate brain-wide network dynamics during post-stroke recovery. Optogenetics is a revolutionary neuroscience tool that uses bioengineered lightsensitive proteins to selectively activate or inhibit specific cell types and neural circuits within milliseconds, allowing greater specificity and temporal precision for dissecting neural circuit mechanisms in diseases. In this review, we discuss the current view of post-stroke remapping and recovery, including recent studies that use optogenetics to investigate neural circuit remapping after stroke, as well as optogenetic stimulation to enhance stroke recovery. Multimodal approaches employing optogenetics in conjunction with other readouts (e.g., in vivo neuroimaging techniques, behavior assays, and next-generation sequencing) will advance our understanding of neural circuit reorganization during post-stroke recovery, as well as provide important insights into which brain circuits to target when designing brain stimulation strategies for future clinical studies.

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“…ATD uses a combination of physical sectioning and deconvolved wide-field imaging to generate an unparalleled combination of acquisition speed, volumetric resolution (100 nm by 100 nm by 50–70 nm) and molecular multiplexing (Wang and Smith, 2012; Micheva and Smith, 2007). Using ATD, different populations of synapses can be classified from large regions of the cortex based on molecular markers (Wang et al, 2014; Micheva et al, 2010; Allen et al, 2012; Hiu et al., 2016). These EM verified algorithms can be used to extract different classes of synapses (excitatory, inhibitory and their subclasses) at large numbers (>1 million) with low error rates (false positive 5%, false negative 12% – for more on antibody verification and error rates see 'Methods') (Wang et al, 2014; Allen et al, 2012; Hiu et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Using ATD, different populations of synapses can be classified from large regions of the cortex based on molecular markers (Wang et al, 2014; Micheva et al, 2010; Allen et al, 2012; Hiu et al., 2016). These EM verified algorithms can be used to extract different classes of synapses (excitatory, inhibitory and their subclasses) at large numbers (>1 million) with low error rates (false positive 5%, false negative 12% – for more on antibody verification and error rates see 'Methods') (Wang et al, 2014; Allen et al, 2012; Hiu et al, 2016). Moreover, these algorithms return the molecular features of each synapse organized around a spatial vector that defines the presynaptic bouton to post-synaptic density (Wang et al, 2014; Allen et al, 2012; Hiu et al, 2016) (see Figure 1E).…”

Section: Introductionmentioning

confidence: 99%

“…These EM verified algorithms can be used to extract different classes of synapses (excitatory, inhibitory and their subclasses) at large numbers (>1 million) with low error rates (false positive 5%, false negative 12% – for more on antibody verification and error rates see 'Methods') (Wang et al, 2014; Allen et al, 2012; Hiu et al, 2016). Moreover, these algorithms return the molecular features of each synapse organized around a spatial vector that defines the presynaptic bouton to post-synaptic density (Wang et al, 2014; Allen et al, 2012; Hiu et al, 2016) (see Figure 1E).

10.7554/eLife.20560.002Figure 1.Multiplexed visualization of synaptic proteins in AT.( A ) Representative maximum (max) projections (25 µm by 20 µm by 1.5 µm) of PSD95, SYN and VGluT1.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sub-synaptic, multiplexed analysis of proteins reveals Fragile X related protein 2 is mislocalized in Fmr1 KO synapses

Wang

Smith

Mourrain

2016

eLife

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The distribution of proteins within sub-synaptic compartments is an essential aspect of their neurological function. Current methodologies, such as electron microscopy (EM) and superresolution imaging techniques, can provide the precise localization of proteins, but are often limited to a small number of one-time observations with narrow spatial and molecular coverage. The diversity of synaptic proteins and synapse types demands synapse analysis on a scale that is prohibitive with current methods. Here, we demonstrate SubSynMAP, a fast, multiplexed subsynaptic protein analysis method using wide-field data from deconvolution array tomography (ATD). SubSynMAP generates probability distributions for that reveal the functional range of proteins within the averaged synapse of a particular class. This enables the differentiation of closely juxtaposed proteins. Using this method, we analyzed 15 synaptic proteins in normal and Fragile X mental retardation syndrome (FXS) model mouse cortex, and revealed disease-specific modifications of sub-synaptic protein distributions across synapse classes and cortical layers.

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Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target

Cited by 100 publications

References 53 publications

Rehabilitation Augments Hematoma Clearance and Attenuates Oxidative Injury and Ion Dyshomeostasis After Brain Hemorrhage

Rehabilitation Augments Hematoma Clearance and Attenuates Oxidative Injury and Ion Dyshomeostasis After Brain Hemorrhage

Optogenetic Approaches to Target Specific Neural Circuits in Post-stroke Recovery

Sub-synaptic, multiplexed analysis of proteins reveals Fragile X related protein 2 is mislocalized in Fmr1 KO synapses

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