scholarly journals Repeated Mild Traumatic Brain Injury Causes Chronic Neuroinflammation, Changes in Hippocampal Synaptic Plasticity, and Associated Cognitive Deficits

2014 ◽  
Vol 34 (7) ◽  
pp. 1223-1232 ◽  
Author(s):  
Stephanie L Aungst ◽  
Shruti V Kabadi ◽  
Scott M Thompson ◽  
Bogdan A Stoica ◽  
Alan I Faden
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Hippocampal Slices ◽  
Neuronal Cell ◽  
Long Term Potentiation ◽  
Cognitive Changes ◽  
Chronic Neuroinflammation ◽  
Term Potentiation

Repeated mild traumatic brain injury (mTBI) can cause sustained cognitive and psychiatric changes, as well as neurodegeneration, but the underlying mechanisms remain unclear. We examined histologic, neurophysiological, and cognitive changes after single or repeated (three injuries) mTBI using the rat lateral fluid percussion (LFP) model. Repeated mTBI caused substantial neuronal cell loss and significantly increased numbers of activated microglia in both ipsilateral and contralateral hippocampus on post-injury day (PID) 28. Long-term potentiation (LTP) could not be induced on PID 28 after repeated mTBI in ex vivo hippocampal slices from either hemisphere. N-Methyl-D-aspartate (NMDA) receptor-mediated responses were significantly attenuated after repeated mTBI, with no significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated responses. Long-term potentiation was elicited in slices after single mTBI, with potentiation significantly increased in ipsilateral versus contralateral hippocampus. After repeated mTBI, rats displayed cognitive impairments in the Morris water maze (MWM) and novel object recognition (NOR) tests. Thus, repeated mTBI causes deficits in the hippocampal function and changes in excitatory synaptic neurotransmission, which are associated with chronic neuroinflammation and neurodegeneration.

Phosphorylation of connexin 43 induced by traumatic brain injury promotes exosome release

2018 ◽  
Vol 119 (1) ◽  
pp. 305-311 ◽  
Author(s):  
Wei Chen ◽  
Yijun Guo ◽  
Wenjin Yang ◽  
Lei Chen ◽  
Dabin Ren ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Gap Junction ◽  
Connexin 43 ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Cx43 Expression ◽  
Term Potentiation ◽  
Junction Protein

Traumatic brain injury (TBI) caused by the external force leads to the neuronal dysfunction and even death. TBI has been reported to significantly increase the phosphorylation of glial gap junction protein connexin 43 (Cx43), which in turn propagates damages into surrounding brain tissues. However, the neuroprotective and anti-apoptosis effects of glia-derived exosomes have also been implicated in recent studies. Therefore, we detected whether TBI-induced phosphorylation of Cx43 would promote exosome release in rat brain. To generate TBI model, adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury. Phosphorylated Cx43 protein levels and exosome activities were quantified using Western blot analysis following TBI. Long-term potentiation (LTP) was also tested in rat hippocampal slices. TBI significantly increased the phosphorylated Cx43 and exosome markers expression in rat ipsilateral hippocampus, but not cortex. Blocking the activity of Cx43 or ERK, but not JNK, significantly suppressed TBI-induced exosome release in hippocampus. Furthermore, TBI significantly inhibited the induction of LTP in hippocampal slices, which could be partially but significantly restored by pretreatment with exosomes. The results imply that TBI-activated Cx43 could mediate a nociceptive effect by propagating the brain damages, as well as a neuroprotective effect by promoting exosome release. NEW & NOTEWORTHY We have demonstrated in rat traumatic brain injury (TBI) models that both phosphorylated connexin 43 (p-Cx43) expression and exosome release were elevated in the hippocampus following TBI. The promoted exosome release depends on the phosphorylation of Cx43 and requires ERK signaling activation. Exosome treatment could partially restore the attenuated long-term potentiation. Our results provide new insight for future therapeutic direction on the functional recovery of TBI by promoting p-Cx43-dependent exosome release but limiting the gap junction-mediated bystander effect.

scholarly journals Proteasome and Autophagy-Mediated Impairment of Late Long-Term Potentiation (l-LTP) after Traumatic Brain Injury in the Somatosensory Cortex of Mice

2019 ◽  
Vol 20 (12) ◽  
pp. 3048 ◽  
Author(s):  
Feldmann ◽  
Le Prieult ◽  
Felzen ◽  
Thal ◽  
Engelhard ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Protein Degradation ◽  
Long Term Potentiation ◽  
Theta Burst Stimulation ◽  
Burst Stimulation ◽  
Ipsilateral Hemisphere ◽  
Term Potentiation ◽  
Theta Burst

Traumatic brain injury (TBI) can lead to impaired cognition and memory consolidation.The acute phase (24–48 h) after TBI is often characterized by neural dysfunction in the vicinity ofthe lesion, but also in remote areas like the contralateral hemisphere. Protein homeostasis is crucialfor synaptic long-term plasticity including the protein degradation systems, proteasome andautophagy. Still, little is known about the acute effects of TBI on synaptic long-term plasticity andprotein degradation. Thus, we investigated TBI in a controlled cortical impact (CCI) model in themotor and somatosensory cortex of mice ex vivo-in vitro. Late long-term potentiation (l-LTP) wasinduced by theta-burst stimulation in acute brain slices after survival times of 1–2 days. Proteinlevels for the plasticity related protein calcium/calmodulin-dependent protein kinase II (CaMKII)was quantified by Western blots, and the protein degradation activity by enzymatical assays. Weobserved missing maintenance of l-LTP in the ipsilateral hemisphere, however not in thecontralateral hemisphere after TBI. Protein levels of CaMKII were not changed but, interestingly,the protein degradation revealed bidirectional changes with a reduced proteasome activity and anincreased autophagic flux in the ipsilateral hemisphere. Finally, LTP recordings in the presence ofpharmacologically modified protein degradation systems also led to an impaired synaptic plasticity:bath-applied MG132, a proteasome inhibitor, or rapamycin, an activator of autophagy, bothadministered during theta burst stimulation, blocked the induction of LTP. These data indicate thatalterations in protein degradation pathways likely contribute to cognitive deficits in the acute phaseafter TBI, which could be interesting for future approaches towards neuroprotective treatmentsearly after traumatic brain injury.

Enduring suppression of hippocampal long-term potentiation following traumatic brain injury in rat

1992 ◽  
Vol 585 (1-2) ◽  
pp. 335-339 ◽  
Author(s):  
S. Miyazaki ◽  
Y. Katayama ◽  
B.G. Lyeth ◽  
L.W. Jenkins ◽  
D.S. DeWitt ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Long Term Potentiation ◽  
Term Potentiation

Ellagic acid prevents cognitive and hippocampal long-term potentiation deficits and brain inflammation in rat with traumatic brain injury

Life Sciences ◽  
2015 ◽  
Vol 124 ◽  
pp. 120-127 ◽  
Author(s):  
Yaghoob Farbood ◽  
Alireza Sarkaki ◽  
Mahin Dianat ◽  
Ali Khodadadi ◽  
Mohammad Khaksari Haddad ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Ellagic Acid ◽  
Long Term Potentiation ◽  
Brain Inflammation ◽  
Term Potentiation

Hydrogen Sulfide in Physiological and Pathological Mechanisms in Brain

2018 ◽  
Vol 17 (9) ◽  
pp. 654-670 ◽  
Author(s):  
Mohit Kumar ◽  
Rajat Sandhir
Keyword(s):  
Nitric Oxide ◽  
Traumatic Brain Injury ◽  
Hydrogen Sulfide ◽  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Scientific Community ◽  
Molecular Targets ◽  
Long Term Potentiation ◽  
Term Potentiation

Background & Objective: Hydrogen sulfide [H2S] has been widely known as a toxic gas for more than 300 years in the scientific community. However, the understanding about this small molecule has changed after the discovery of involvement of H2S in physiological and pathological mechanisms in brain. H2S is a third gasotransmitter and neuromodulator after carbon monoxide [CO] and nitric oxide [NO]. H2S plays an important role in memory and cognition by regulating long-term potentiation [LTP] and calcium homeostasis in neuronal cells. The disturbances in endogenous H2S levels and trans-sulfuration pathway have been implicated in neurodegenerative disorders like Alzheimer’s disease, Parkinson disease, stroke and traumatic brain injury. According to the results obtained from various studies, H2S not only behaves as neuromodulator but also is a potent antioxidant, anti-inflammatory and anti-apoptotic molecule suggesting its neuroprotective potential. Conclusion: Recently, there is an increased interest in developing H2S releasing pharmaceuticals to target various neurological disorders. This review covers the information about the involvement of H2S in neurodegenerative diseases, its molecular targets and its role as potential therapeutic molecule.

scholarly journals GPR110 ligands reduce chronic optic tract gliosis and visual deficit following repetitive mild traumatic brain injury in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Huazhen Chen ◽  
Karl Kevala ◽  
Elma Aflaki ◽  
Juan Marugan ◽  
Hee-Yong Kim
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Visual Evoked Potential ◽  
Evoked Potential ◽  
Optic Tract ◽  
Primary Microglia ◽  
Visual Dysfunction ◽  
The Brain

Abstract Background Repetitive mild traumatic brain injury (mTBI) can result in chronic visual dysfunction. G-protein receptor 110 (GPR110, ADGRF1) is the target receptor of N-docosahexaenoylethanolamine (synaptamide) mediating the anti-neuroinflammatory function of synaptamide. In this study, we evaluated the effect of an endogenous and a synthetic ligand of GPR110, synaptamide and (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-hydroxy-2-methylpropyl) docosa-4,7,10,13,16,19-hexaenamide (dimethylsynaptamide, A8), on the mTBI-induced long-term optic tract histopathology and visual dysfunction using Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA), a clinically relevant model of mTBI. Methods The brain injury in wild-type (WT) and GPR110 knockout (KO) mice was induced by CHIMERA applied daily for 3 days, and GPR110 ligands were intraperitoneally injected immediately following each impact. The expression of GPR110 and proinflammatory mediator tumor necrosis factor (TNF) in the brain was measured by using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in an acute phase. Chronic inflammatory responses in the optic tract and visual dysfunction were assessed by immunostaining for Iba-1 and GFAP and visual evoked potential (VEP), respectively. The effect of GPR110 ligands in vitro was evaluated by the cyclic adenosine monophosphate (cAMP) production in primary microglia isolated from adult WT or KO mouse brains. Results CHIMERA injury acutely upregulated the GPR110 and TNF gene level in mouse brain. Repetitive CHIMERA (rCHIMERA) increased the GFAP and Iba-1 immunostaining of glia cells and silver staining of degenerating axons in the optic tract with significant reduction of N1 amplitude of visual evoked potential at up to 3.5 months after injury. Both GPR110 ligands dose- and GPR110-dependently increased cAMP in cultured primary microglia with A8, a ligand with improved stability, being more effective than synaptamide. Intraperitoneal injection of A8 at 1 mg/kg or synaptamide at 5 mg/kg significantly reduced the acute expression of TNF mRNA in the brain and ameliorated chronic optic tract microgliosis, astrogliosis, and axonal degeneration as well as visual deficit caused by injury in WT but not in GPR110 KO mice. Conclusion Our data demonstrate that ligand-induced activation of the GPR110/cAMP system upregulated after injury ameliorates the long-term optic tract histopathology and visual impairment caused by rCHIMERA. Based on the anti-inflammatory nature of GPR110 activation, we suggest that GPR110 ligands may have therapeutic potential for chronic visual dysfunction associated with mTBI.

Sign in / Sign up

Export Citation Format

Share Document