Adenosine A2A Receptor Deficiency Alleviates Blast-Induced Cognitive Dysfunction

Ning, Yuping; Yang, Nan; Chen, Xing; Xiong, Ranhua; Zhang, Xiu-Zhu; Li, Ping; Zhao, Yan; Chen, Xingyun; Liu, Ping; Peng, Yan; Wang, Zhengguo; Chen, Jiang‐Fan; Zhou, Yuan‐Guo

doi:10.1038/jcbfm.2013.127

Cited by 43 publications

(32 citation statements)

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“…This approach is different from past work that often focused on one type of behavioral deficit, whether it was related to anxiety (Patel et al, 2014a; Xie et al, 2013; Yin et al, 2014), memory (Ning et al, 2013; Rubovitch et al, 2011), or motor impairment (del Mar et al, 2015). With our interest in primary blast loading, we focused on understanding a deficit in spatial object recognition that remained even when the head was restrained during blast exposure.…”

Section: Discussionmentioning

confidence: 90%

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

Beamer¹,

Tummala²,

Gullotti³

et al. 2016

Experimental Neurology

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Blast-induced traumatic brain injury (bTBI) and its long term consequences are a major health concern among veterans. Despite recent work enhancing our knowledge about bTBI, very little is known about the contribution of the blast wave alone to the observed sequelae. Herein, we isolated its contribution in a mouse model by constraining the animals' heads during exposure to a shockwave (primary blast). Our results show that exposure to primary blast alone results in changes in hippocampus-dependent behaviors that correspond with electro-physiological changes in area CA1 and are accompanied by reactive gliosis. Specifically, five days after exposure, behavior in an open field and performance in a spatial object recognition (SOR) task were significantly different from sham. Network electrophysiology, also performed five days after injury, demonstrated a significant decrease in excitability and increase in inhibitory tone. Immunohistochemistry for GFAP and Iba1 performed ten days after injury showed a significant increase in staining. Interestingly, a threefold increase in the impulse of the primary blast wave did not exacerbate these measures. However, we observed a significant reduction in the contribution of the NMDA receptors to the field EPSP at the highest blast exposure level. Our results emphasize the need to account for the effects of primary blast loading when studying the sequelae of bTBI.

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Section: Discussionmentioning

confidence: 90%

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

Beamer¹,

Tummala²,

Gullotti³

et al. 2016

Experimental Neurology

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“…A reduction of A2a receptors in mice with traumatic brain injury has also been shown to decrease cognitive impairment (Ning, Yang et al 2013). In fact, the adenosine 2a receptor localizes in microglial cells and may be a regulation of microglial function in response to brain damage (Cunha, Ferre et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease

Horgusluoglu‐Moloch

Nho

Risacher

et al. 2017

Neurobiology of Aging

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Alzheimer’s disease (AD) patients display hippocampal atrophy, memory impairment, and cognitive decline. New neurons are generated throughout adulthood in two regions of the brain implicated in AD, the dentate gyrus of the hippocampus and the sub-ventricular zone of the olfactory bulb. Disruption of this process contributes to neurodegenerative diseases including AD and many of the molecular players in AD are also modulators of adult neurogenesis. However, the genetic mechanisms underlying adult neurogenesis in AD have been underexplored. To address this gap, we performed a gene-based association analysis in cognitively normal and impaired participants using neurogenesis pathway-related candidate genes curated from existing databases, literature mining, and large-scale genome-wide association study findings. A gene-based association analysis identified ADORA2A as significantly associated with hippocampal volume and the association between rs9608282 within ADORA2A and hippocampal volume was replicated in the meta-analysis after multiple comparison adjustments (p=7.88×10−6). The minor allele of rs9608282 in ADORA2A is associated with larger hippocampal volumes and better memory.

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“…; Ning et al . ). Also, A 2A R blockade, either upon genetic deletion or using selective A 2A R antagonists attenuates the escalating severity of seizures (El Yacoubi et al .…”

Section: The Role Of A2ar In Neuroprotectionmentioning

confidence: 97%

How does adenosine control neuronal dysfunction and neurodegeneration?

Cunha

2016

Journal of Neurochemistry

368

385

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The adenosine modulation system mostly operates through inhibitory A 1 (A 1 R) and facilitatory A 2A receptors (A 2A R) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A 1 R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: highfrequency stimulation triggers ATP release in the 'activated' synapse, which is locally converted by ecto-nucleotidases into adenosine to selectively activate A 2A R; A 2A R switch off A 1 R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the 'activated' synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A 1 R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near-threshold and/or of short-duration, A 1 R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A 2A R, probably to bolster adaptive changes, but this heightens brain damage since A 2A R blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A 2A R, whereas astrocytic and microglia A 2A R might control the spread of damage. The A 2A R signaling mechanisms are largely unknown since A 2A R are pleiotropic, coupling to different G proteins and non-canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A 1 R preconditioning and preventing excessive A 2A R function might afford maximal neuroprotection. Keywords: A 1 receptor, A 2A receptor, astrocyte, microglia, synaptic plasticity, synaptotoxicity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Relevance of modulation systems to tune information flow in brain circuitsThe goal of understanding the flow of information in neuronal circuits has traditionally been centered in studying the key processes sustaining synaptic transmission and plasticity -i.e. the role of glutamate and glutamate receptors, as well as to a lesser extent the role of GABA and its receptors. If one considers an analogy to the experience of watching TV, this corresponds to studying how the ON/OFF button impacts all Received April 4, 2016; revised manuscript received May 23, 2016; accepted June 23, 2016. Address correspondence and reprint requests to R. A. Cunha, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. E-mail: cunharod@gmail.com Abbreviations used: A 1 R, adenosine A 1 receptor; A 2A R, adenosine A 2A receptor; ADHD, attention deficit and hyperactivity disorder; BDNF, brain-derived neurotrophi...

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Adenosine A2A Receptor Deficiency Alleviates Blast-Induced Cognitive Dysfunction

Cited by 43 publications

References 40 publications

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease

How does adenosine control neuronal dysfunction and neurodegeneration?

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