Progressive loss of phasic, but not tonic, GABAA receptor-mediated inhibition in dentate granule cells in a model of post-traumatic epilepsy in rats

Pavlov, Ivan; Huusko, Noora; Drexel, Meinrad; Kirchmair, Elke; Sperk, Günther; Pitkänen, Asla; Walker, Matthew C.

doi:10.1016/j.neuroscience.2011.07.074

Cited by 90 publications

(116 citation statements)

References 55 publications

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“…Results of a recent study conducted 3 months after cortical-impact injury indicate that granule cell tonic GABA currents are elevated on the side contralateral to injury (Mtchedlishvili et al, 2010). However, granule cell tonic GABA currents were not enhanced 1-6 months after severe fluid percussion injury (Pavlov et al, 2011). We examined whether brain injury leads to early changes in granule cell tonic GABA currents when the dentate network shows increases in perforant path-evoked excitability.…”

Section: Brain Injury Decreases Sgc Tonic Gaba Currentsmentioning

confidence: 97%

Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury

Gupta¹,

Elgammal²,

Proddutur³

et al. 2012

J. Neurosci.

104

234

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Brain injury is an etiological factor for temporal lobe epilepsy and can lead to memory and cognitive impairments. A recently characterized excitatory neuronal class in the dentate molecular layer, semilunar granule cell (SGC), has been proposed to regulate dentate network activity patterns and working memory formation. Although SGCs, like granule cells, project to CA3, their typical sustained firing and associational axon collaterals suggest that they are functionally distinct from granule cells. We find that brain injury results in an enhancement of SGC excitability associated with an increase in input resistance 1 week after trauma. In addition to prolonging miniature and spontaneous IPSC interevent intervals, brain injury significantly reduces the amplitude of tonic GABA currents in SGCs. The postinjury decrease in SGC tonic GABA currents is in direct contrast to the increase observed in granule cells after trauma. Although our observation that SGCs express Prox1 indicates a shared lineage with granule cells, data from control rats show that SGC tonic GABA currents are larger and sIPSC interevent intervals shorter than in granule cells, demonstrating inherent differences in inhibition between these cell types. GABA A receptor antagonists selectively augmented SGC input resistance in controls but not in head-injured rats. Moreover, post-traumatic differences in SGC firing were abolished in GABA A receptor blockers. Our data show that cell-type-specific post-traumatic decreases in tonic GABA currents boost SGC excitability after brain injury. Hyperexcitable SGCs could augment dentate throughput to CA3 and contribute substantively to the enhanced risk for epilepsy and memory dysfunction after traumatic brain injury.

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Section: Brain Injury Decreases Sgc Tonic Gaba Currentsmentioning

confidence: 97%

Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury

Gupta¹,

Elgammal²,

Proddutur³

et al. 2012

J. Neurosci.

104

234

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“…Previous experimental studies showed that N-methyl-D-aspartate (NMDA) glutamate receptors contribute to several post-TBI pathologies that lead to functional impairments, including hypoperfusion due to failure in cerebrovascular autoregulation (7), edema via accumulation of intracellular Na 1 (8,9), glutamate-induced excitotoxicity (10), epileptogenesis (11), and cognitive decline (12). Similarly, inhibitory g-aminobutyric acid (GABA)-A receptor-mediated functions contribute to the development and expression of post-TBI aftermath, particularly to excitability related to acute seizures and epileptogenesis (11)(12)(13)(14). To date, no PET ligands have been available for assessment of the expression of NMDA or GABA-A receptors during the disease process.…”

mentioning

confidence: 99%

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography

et al. 2016

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In vivo imaging of N-methyl-D-aspartate (NMDA) glutamate receptor and γ-aminobutyric acid (GABA)-A receptor during progression of brain pathology is challenging because of the lack of imaging tracers with high affinity and specificity. Methods: We monitored changes in NMDA receptor and GABA-A receptor in a clinically relevant model of traumatic brain injury (TBI) induced by lateral fluid percussion in adult rats, using 2 new ligands for PET: 18 F-GE-179 for the open/active state of the NMDA receptor ion channel and 18 F-GE-194 for GABA-A receptor. Ex vivo brain autoradiography of radioligands was performed at subacute (5-6 d) and chronic (40-42 d) time points after TBI. Results: At 5-6 d after TBI, 18 F-GE-179 binding was higher in the cortical lesion area, in the lesion core, and in the hippocampus than in the corresponding contralateral regions; this increase was probably related to increased permeability of the blood-brain barrier. At 40-42 d after TBI, 18 F-GE-179 binding was significantly higher in the medial cortex, in the corpus callosum, and in the thalamus than in the corresponding contralateral regions. Five to 6 days after TBI, 18 F-GE-194 binding was significantly higher in the lesion core and significantly lower in the ipsilateral thalamus. By 40-42 d after TBI, the reduction in 18 F-GE-194 binding extended to the cortical lesion, including the perilesional cortex around the lesion core. The reduction in thalamic binding was more extensive at 40-42 d than at 5-6 d after TBI, suggesting a progressive decrease in thalamic GABA-A receptor density. Immunohistochemistry against GABA-A α1 subunit revealed a similar decrease to 18 F-GE-194 binding, particularly during the chronic phase. Conclusion: Our data support the validity of novel 18 F-GE-179 and 18 F-GE-194 radioligands for the detection of changes in active NMDA receptor and GABA-A receptor in the injured brain. These tools are useful for follow-up evaluation of secondary postinjury pathologies.

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“…Severe TBI leads to reduction of the GABAA-mediated inhibitory transmission in dentate granule cells (DGCs) in rats (205; 221) and mice (322). Both, evoked (322) and spontaneous (205; 221; 322) miniature inhibitory postsynaptic currents (mIPSC) are less frequent in DGCs after severe TBI, which was associated with loss of parvalbumin-positive interneurons (221). However, the study of mTBI impact in the hippocampal inhibitory GABAergic synaptic transmission is not clear and more studies are needed to elucidate mechanisms that are envolved in the functional pathology.…”

Section: Chapter 4: Specific Loss Of Interneurons and Reduced Gabaergmentioning

confidence: 99%

Pathological and Pathophysiological Alterations in Temporal Lobe Structures After Mild Traumatic Brain Injury

Almeida¹,

Camila²

2014

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Progressive loss of phasic, but not tonic, GABAA receptor-mediated inhibition in dentate granule cells in a model of post-traumatic epilepsy in rats

Cited by 90 publications

References 55 publications

Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury

Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography

Pathological and Pathophysiological Alterations in Temporal Lobe Structures After Mild Traumatic Brain Injury

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Progressive loss of phasic, but not tonic, GABAA receptor-mediated inhibition in dentate granule cells in a model of post-traumatic epilepsy in rats

Cited by 90 publications

References 55 publications

Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury

Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using 18F-GE-179 and 18F-GE-194 Autoradiography

Pathological and Pathophysiological Alterations in Temporal Lobe Structures After Mild Traumatic Brain Injury

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Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography