Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling

Nagendran, T; Larsen, Rylan S.; Bigler, Rebecca L.; Frost, Shawn B.; Philpot, Benjamin D.; Nudo, Randolph J.; Taylor, Anne Marion

doi:10.1101/065391

Cited by 3 publications

(15 citation statements)

References 67 publications

(51 reference statements)

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“…Primarily axons of pyramidal neurons are guided via microgrooves into a separated axon compartment where they are injured and various pharmacological treatments can be restricted to isolated axons. We previously found that blocking local activity at the site of injury using this method prevented dendritic spine loss 24 h post-axotomy (Nagendran et al 2017), suggesting calcium and sodium influx at the site of injury are key mediators of this neuronal injury response. Reversal of NCX at the site of injury may play a key role, causing this massive local influx of calcium.…”

Section: Resultsmentioning

confidence: 99%

“…Axon injury induces differential gene expression and transcription within the soma, requiring long range signaling from the site of injury to the nucleus (Rishal and Fainzilber 2014; Nagendran et al 2017). Breach of the axonal membrane following axon injury causes an influx of ions, including calcium and sodium, into the intra-axonal space.…”

Section: Introductionmentioning

confidence: 99%

“…Axotomy performed within compartmentalized platforms produced several characteristic injury responses well described in vivo , including rapid expression of the immediate early gene c-fos (Taylor et al 2005) and reduced expression of netrin-1 one day following axon damage. Evidence of ER changes within the soma, called chromatolysis, occurs in axotomized neurons in vitro (McIlwain and Hoke 2005; Nagendran et al 2017). Axotomized neurons within microfluidic chambers also showed that dendritic spine loss (Nagendran et al, 2017)(Gao et al 2011; Ghosh et al 2012) and hyper-excitability (Frost et al 2015; Nagendran et al 2017) occur, providing an experimentally tractable model to study initiation and progression of these neuronal injury responses.…”

Section: Introductionmentioning

confidence: 99%

“…Evidence of ER changes within the soma, called chromatolysis, occurs in axotomized neurons in vitro (McIlwain and Hoke 2005; Nagendran et al 2017). Axotomized neurons within microfluidic chambers also showed that dendritic spine loss (Nagendran et al, 2017)(Gao et al 2011; Ghosh et al 2012) and hyper-excitability (Frost et al 2015; Nagendran et al 2017) occur, providing an experimentally tractable model to study initiation and progression of these neuronal injury responses. Axotomy within these platforms produced a delayed enhancement in neuronal hyper-excitability, one day following dendritic spine loss.…”

Section: Introductionmentioning

confidence: 99%

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Unique axon-to-soma signaling pathways mediate dendritic spine loss and hyper-excitability post-axotomy

Nagendran

Taylor

2019

Preprint

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Axon damage may cause axon regeneration, retrograde synapse loss, and hyper-excitability, all of which affect recovery following acquired brain injury. While axon regeneration is studied extensively, less is known about signaling mediating retrograde synapse loss and hyper-excitability, especially in long projection pyramidal neurons. To investigate intrinsic injury signaling within neurons, we use an in vitro microfluidic platform that models dendritic spine loss and delayed hyper-excitability following remote axon injury. Our data show that sodium influx and reversal of sodium calcium exchangers (NCXs) at the site of axotomy, mediate dendritic spine loss following axotomy. In contrast, sodium influx and NCX reversal alone are insufficient to cause retrograde hyper-excitability. We found that calcium release from axonal ER is critical for the induction of hyper-excitability and inhibition loss. These data suggest that synapse loss and hyper-excitability are uncoupled responses following axon injury. Further, axonal ER may play a critical and underappreciated role in mediating retrograde hyper-excitability within the CNS.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Unique axon-to-soma signaling pathways mediate dendritic spine loss and hyper-excitability post-axotomy

Nagendran

Taylor

2019

Preprint

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“…Microfluidic cultures were immunostained to detect phospho-cJun (pcJun) and Neurofilament. The retrograde signaling is tracked from uninjured and injured axon chambers on either side to the central cell body chamber (Holland et al, 2016) range axotomy (Nagendran et al, 2017). Using microgrooves 900 μm in length, Nakatomi et al (2002) examined the effect of axotomy on synaptic remodeling similar to in vivo conditions where long projection neurons are affected far from the site of CNS injury.…”

Section: Et Al (2012)mentioning

confidence: 99%

Microfluidic platforms for the study of neuronal injury in vitro

Shrirao

Kung

Omelchenko

et al. 2018

Biotech & Bioengineering

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Traumatic brain injury (TBI) affects 5.3 million people in the United States, and there are 12,500 new cases of spinal cord injury (SCI) every year. There is yet a significant need for in vitro models of TBI and SCI in order to understand the biological mechanisms underlying central nervous system (CNS) injury and to identify and test therapeutics to aid in recovery from neuronal injuries. While TBI or SCI studies have been aided with traditional in vivo and in vitro models, the innate limitations in specificity of injury, isolation of neuronal regions, and reproducibility of these models can decrease their usefulness in examining the neurobiology of injury. Microfluidic devices provide several advantages over traditional methods by allowing researchers to (1) examine the effect of injury on specific neural components, (2) fluidically isolate neuronal regions to examine specific effects on subcellular components, and (3) reproducibly create a variety of injuries to model TBI and SCI. These microfluidic devices are adaptable for modeling a wide range of injuries, and in this review, we will examine different methodologies and models recently utilized to examine neuronal injury. Specifically, we will examine vacuum-assisted axotomy, physical injury, chemical injury, and laser-based axotomy. Finally, we will discuss the benefits and downsides to each type of injury model and discuss how researchers can use these parameters to pick a particular microfluidic device to model CNS injury.

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Microfluidic Surgery in Single Cells and Multicellular Systems

Zhang¹,

Nadkarni²,

Paul³

et al. 2021

Preprint

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Microscale surgery on single cells and small organisms have enabled major advances in fundamental biology and in engineering biological systems. Examples of applications range from wound healing and regeneration studies to the generation of hybridoma to produce monoclonal antibodies. Even today, these surgical operations are often performed manually, but they are labor-intensive and lack reproducibility. Microfluidics has emerged as a powerful technology to control and manipulate cells and multicellular systems at the micro- and nanoscale with high precision. Here, we review the physical and chemical mechanisms of microscale surgery, and the corresponding design principles, applications, and implementations in microfluidic systems. We consider four types of surgical operations: 1) Sectioning, which splits a biological entity into multiple parts, 2) ablation, which destroys part of an entity, 3) biopsy, which extracts materials from within a living cell, and 4) fusion, which joins multiple entities into one. For each type of surgery, we summarize the motivating applications and the microfluidic devices developed. Throughout the review, we highlight existing challenges and opportunities. We hope that this review will inspire scientists and engineers to continue to explore and improve microfluidic surgical methods.

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Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling

Cited by 3 publications

References 67 publications

Unique axon-to-soma signaling pathways mediate dendritic spine loss and hyper-excitability post-axotomy

Unique axon-to-soma signaling pathways mediate dendritic spine loss and hyper-excitability post-axotomy

Microfluidic platforms for the study of neuronal injury in vitro

Microfluidic Surgery in Single Cells and Multicellular Systems

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