scholarly journals Blockade of TRPC Channels Limits Cholinergic-Driven Hyperexcitability and Seizure Susceptibility After Traumatic Brain Injury

2021 ◽  
Vol 15 ◽  
Author(s):  
Chase M. Carver ◽  
Haley R. DeWitt ◽  
Aiola P. Stoja ◽  
Mark S. Shapiro
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Dentate Gyrus ◽  
Transient Receptor Potential ◽  
Brain Slices ◽  
Receptor Activation ◽  
Cholinergic Innervation ◽  
Trpc Channels ◽  
Seizure Susceptibility ◽  
Male Adult

We investigated the contribution of excitatory transient receptor potential canonical (TRPC) cation channels to posttraumatic hyperexcitability in the brain 7 days following controlled cortical impact model of traumatic brain injury (TBI) to the parietal cortex in male adult mice. We investigated if TRPC1/TRPC4/TRPC5 channel expression is upregulated in excitatory neurons after TBI in contribution to epileptogenic hyperexcitability in key hippocampal and cortical circuits that have substantial cholinergic innervation. This was tested by measuring TRPC1/TRPC4/TRPC5 protein and messenger RNA (mRNA) expression, assays of cholinergic function, neuronal Ca2+ imaging in brain slices, and seizure susceptibility after TBI. We found region-specific increases in expression of TRPC1, TRPC4, and TRPC5 subunits in the hippocampus and cortex following TBI. The dentate gyrus, CA3 region, and cortex all exhibited robust upregulation of TRPC4 mRNA and protein. TBI increased cFos activity in dentate gyrus granule cells (DGGCs) and layer 5 pyramidal neurons both at the time of TBI and 7 days post-TBI. DGGCs displayed greater magnitude and duration of acetylcholine-induced rises in intracellular Ca2+ in brain slices from mice subjected to TBI. The TBI mice also exhibited greater seizure susceptibility in response to pentylenetetrazol-induced kindling. Blockade of TRPC4/TRPC5 channels with M084 reduced neuronal hyperexcitation and impeded epileptogenic progression of kindling. We observed that the time-dependent upregulation of TRPC4/TRPC5-containing channels alters cholinergic responses and activity of principal neurons acting to increase proexcitatory sensitivity. The underlying mechanism includes acutely decreased acetylcholinesterase function, resulting in greater Gq/11-coupled muscarinic receptor activation of TRPC channels. Overall, our evidence suggests that TBI-induced plasticity of TRPC channels strongly contributes to overt hyperexcitability and primes the hippocampus and cortex for seizures.

scholarly journals Peripheral Infection after Traumatic Brain Injury Augments Excitability in the Perilesional Cortex and Dentate Gyrus

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1946
Author(s):  
Ying Wang ◽  
Pedro Andrade ◽  
Asla Pitkänen
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Dentate Gyrus ◽  
Sham Operation ◽  
Seizure Susceptibility ◽  
Neuronal Activation ◽  
Post Injury ◽  
Ptz Test ◽  
Peripheral Infection ◽  
Lps Treatment

Peripheral infections occur in up to 28% of patients with traumatic brain injury (TBI), which is a major etiology for structural epilepsies. We hypothesized that infection occurring after TBI acts as a “second hit” and facilitates post-traumatic epileptogenesis. Adult male Sprague–Dawley rats were subjected to lateral fluid-percussion injury or sham-operation. At 8 weeks post-injury, rats were treated with lipopolysaccharide (LPS, 5 mg/kg) to mimic Gram-negative peripheral infection. T2-weighted magnetic resonance imaging was used to detect the cortical lesion type (small focal inflammatory [TBIFI] vs. large cavity-forming [TBICF]). Spontaneous seizures were detected with video-electroencephalography, and seizure susceptibility was determined by the pentylenetetrazole (PTZ) test. Post-PTZ neuronal activation was assessed using c-Fos immunohistochemistry. LPS treatment increased the percentage of rats with PTZ-induced seizures among animals with TBIFI lesions (p < 0.05). It also increased the cumulative duration of PTZ-induced seizures (p < 0.01), particularly in the TBIFI group (p < 0.05). The number of c-Fos immunopositive cells was higher in the perilesional cortex of injured animals compared with sham-operated animals (p < 0.05), particularly in the TBI-LPS group (p < 0.05). LPS treatment increased the percentage of injured rats with bilateral c-Fos staining in the dentate gyrus (p < 0.05), particularly in the TBIFI group (p < 0.05). Our findings demonstrate that peripheral infection after TBI increases PTZ-induced seizure susceptibility and neuronal activation in the perilesional cortex and bilaterally in the dentate gyrus, particularly in animals with prolonged perilesional T2 enhancement. Our data suggest that treatment of infections and reduction of post-injury neuro-inflammation are important components of the treatment regimen aiming at preventing epileptogenesis after TBI.

scholarly journals Enhancement of Neurogenesis and Memory by a Neurotrophic Peptide in Mild to Moderate Traumatic Brain Injury

Neurosurgery ◽  
2014 ◽  
Vol 76 (2) ◽  
pp. 201-215 ◽  
Author(s):  
Muhammad Omar Chohan ◽  
Olga Bragina ◽  
Syed Faraz Kazim ◽  
Gloria Statom ◽  
Narjes Baazaoui ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Dentate Gyrus ◽  
Parietal Cortex ◽  
Saline Solution ◽  
Neuronal Loss ◽  
Synaptic Density ◽  
Moderate Traumatic Brain Injury ◽  
Long Term Treatment ◽  
Newborn Neurons

ABSTRACT BACKGROUND: Traumatic brain injury (TBI) is a risk factor for Alzheimer disease (AD), a neurocognitive disorder with similar cellular abnormalities. We recently discovered a small molecule (Peptide 6) corresponding to an active region of human ciliary neurotrophic factor, with neurogenic and neurotrophic properties in mouse models of AD and Down syndrome. OBJECTIVE: To describe hippocampal abnormalities in a mouse model of mild to moderate TBI and their reversal by Peptide 6. METHODS: TBI was induced in adult C57Bl6 mice using controlled cortical impact with 1.5 mm of cortical penetration. The animals were treated with 50 nmol/d of Peptide 6 or saline solution for 30 days. Dentate gyrus neurogenesis, dendritic and synaptic density, and AD biomarkers were quantitatively analyzed, and behavioral tests were performed. RESULTS: Ipsilateral neuronal loss in CA1 and the parietal cortex and increase in Alzheimer-type hyperphosphorylated tau and A-β were seen in TBI mice. Compared with saline solution, Peptide 6 treatment increased the number of newborn neurons, but not uncommitted progenitor cells, in dentate gyrus by 80%. Peptide 6 treatment also reversed TBI-induced dendritic and synaptic density loss while increasing activity in tri-synaptic hippocampal circuitry, ultimately leading to improvement in memory recall on behavioral testing. CONCLUSION: Long-term treatment with Peptide 6 enhances the pool of newborn neurons in the dentate gyrus, prevents neuronal loss in CA1 and parietal cortex, preserves the dendritic and synaptic architecture in the hippocampus, and improves performance on a hippocampus-dependent memory task in TBI mice. These findings necessitate further inquiry into the therapeutic potential of small molecules based on neurotrophic factors.

scholarly journals Physiological and Structural Evidence for Hippocampal Involvement in Persistent Seizure Susceptibility after Traumatic Brain Injury

2001 ◽  
Vol 21 (21) ◽  
pp. 8523-8537 ◽  
Author(s):  
Golijeh Golarai ◽  
Anders C. Greenwood ◽  
Dennis M. Feeney ◽  
John A. Connor
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Seizure Susceptibility

scholarly journals Effects of Transient Receptor Potential Cation 5 (TRPC5) Inhibitor, NU6027, on Hippocampal Neuronal Death after Traumatic Brain Injury

2020 ◽  
Vol 21 (21) ◽  
pp. 8256 ◽  
Author(s):  
Min Kyu Park ◽  
Bo Young Choi ◽  
A Ra Kho ◽  
Song Hee Lee ◽  
Dae Ki Hong ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Death ◽  
Transient Receptor Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Treated Group ◽  
Therapeutic Window ◽  
Permanent Disability ◽  
Fluoro Jade B

Traumatic brain injury (TBI) can cause physical, cognitive, social, and behavioral changes that can lead to permanent disability or death. After primary brain injury, translocated free zinc can accumulate in neurons and lead to secondary events such as oxidative stress, inflammation, edema, swelling, and cognitive impairment. Under pathological conditions, such as ischemia and TBI, excessive zinc release, and accumulation occurs in neurons. Based on previous research, it hypothesized that calcium as well as zinc would be influx into the TRPC5 channel. Therefore, we hypothesized that the suppression of TRPC5 would prevent neuronal cell death by reducing the influx of zinc and calcium. To test our hypothesis, we used a TBI animal model. After the TBI, we immediately injected NU6027 (1 mg/kg, intraperitoneal), TRPC5 inhibitor, and then sacrificed animals 24 h later. We conducted Fluoro-Jade B (FJB) staining to confirm the presence of degenerating neurons in the hippocampal cornus ammonis 3 (CA3). After the TBI, the degenerating neuronal cell count was decreased in the NU6027-treated group compared with the vehicle-treated group. Our findings suggest that the suppression of TRPC5 can open a new therapeutic window for a reduction of the neuronal death that may occur after TBI.

scholarly journals Neurotensin inhibits both dopamine- and GABA-mediated inhibition of ventral tegmental area dopamine neurons

2015 ◽  
Vol 114 (3) ◽  
pp. 1734-1745 ◽  
Author(s):  
Katherine Stuhrman ◽  
Aaron G. Roseberry
Keyword(s):  
Ventral Tegmental Area ◽  
Calcium Release ◽  
Transient Receptor Potential ◽  
Brain Slices ◽  
Receptor Activation ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Inward Current ◽  
Ventral Tegmental

Dopamine is an essential neurotransmitter that plays an important role in a number of different physiological processes and disorders. There is substantial evidence that the neuropeptide neurotensin interacts with the mesolimbic dopamine system and can regulate dopamine neuron activity. In these studies we have used whole cell patch-clamp electrophysiology in brain slices from mice to examine how neurotensin regulates dopamine neuron activity by examining the effect of neurotensin on the inhibitory postsynaptic current generated by somatodendritic dopamine release (D2R IPSC) in ventral tegmental area (VTA) dopamine neurons. Neurotensin inhibited the D2R IPSC and activated an inward current in VTA dopamine neurons that appeared to be at least partially mediated by activation of a transient receptor potential C-type channel. Neither the inward current nor the inhibition of the D2R IPSC was affected by blocking PKC or calcium release from intracellular stores, and the inhibition of the D2R IPSC was greater with neurotensin compared with activation of other Gq-coupled receptors. Interestingly, the effects of neurotensin were not specific to D2R signaling as neurotensin also inhibited GABAB inhibitory postsynaptic currents in VTA dopamine neurons. Finally, the effects of neurotensin were significantly larger when intracellular Ca2+ was strongly buffered, suggesting that reduced intracellular calcium facilitates these effects. Overall these results suggest that neurotensin may inhibit the D2R and GABAB IPSCs downstream of receptor activation, potentially through regulation of G protein-coupled inwardly rectifying potassium channels. These studies provide an important advance in our understanding of dopamine neuron activity and how it is controlled by neurotensin.

scholarly journals Changes in TrkB–ERK1/2–CREB/Elk-1 Pathways in Hippocampal Mossy Fiber Organization after Traumatic Brain Injury

2004 ◽  
Vol 24 (8) ◽  
pp. 934-943 ◽  
Author(s):  
Bingren Hu ◽  
Chunli Liu ◽  
Helen Bramlett ◽  
Thomas J. Sick ◽  
Ofelia F. Alonso ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Dentate Gyrus ◽  
Signaling Pathways ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Control Level ◽  
Mossy Fibers ◽  
Underlying Mechanism ◽  
Fiber Organization

Traumatic brain injury (TBI) leads to mossy fiber reorganization, which is considered to be a causative factor in the development of temporal lobe epilepsy. However, the underlying mechanism is not fully understood. Emerging evidence suggests that TrkB–ERK1/2–CREB/Elk-1 pathways are highly related to synaptic plasticity. This study used the rat fluid-percussion injury model to investigate activation of TrkB–ERK1/2–CREB/Elk-1 signaling pathways after TBI. Rats were subjected to 2.0-atm parasagittal TBI followed by 30 minutes, 4 hours, 24 hours, and 72 hours of recovery. After TBI, striking activation of TrkB–ERK1/2–CREB/Elk-1 signaling pathways in mossy fiber organization were observed with confocal microscopy and Western blot analysis. ERK1/2 was highly phosphorylated predominantly in hippocampal mossy fibers, whereas TrkB was phosphorylated both in the mossy fibers and the dentate gyrus region at 30 minutes and 4 hours of recovery after TBI. CREB was also activated at 30 minutes, peaked at 24 hours of recovery, and returned to the control level at 72 hours of recovery in dentate gyrus granule cells. Elk-1 phosphorylation was seen in CA3 neurons at 4 hours after TBI. The results suggest that the signaling pathways of TrkB–ERK1/2–CREB/Elk-1 are highly activated in mossy fiber organization, which may contribute to mossy fiber reorganization seen after TBI.

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