GABA receptors in brain development, function, and injury

Wu, Connie; Sun, Dandan

doi:10.1007/s11011-014-9560-1

Cited by 249 publications

(192 citation statements)

References 90 publications

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“…The immature rat brain is particularly sensitive to excitotoxicity in the neonatal period [80,81]. This is regulated, in part, by developmental changes in expression of the NR2A and NR2B subunits of the NMDA receptor [82,83] and/or GABAergic neurotransmission impairments through, for example, cortical loss of GABAergic interneurons [84,85]. In the second and third postnatal weeks, however, this effect is reduced.…”

Section: Age-at-injury Response To Preclinical Tbimentioning

confidence: 99%

Age-Dependent Responses Following Traumatic Brain Injury

Brickler¹,

Morton²,

Hazy³

et al. 2018

Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

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Traumatic brain injury (TBI) is a growing health concern worldwide that affects a broad range of the population. As TBI is the leading cause of disability and mortality in children, several preclinical models have been developed using rodents at a variety of different ages; however, key brain maturation events are overlooked that leave some age groups more or less vulnerable to injury. Thus, there has been a large emphasis on producing relevant animal models to elucidate molecular pathways that could be of therapeutic potential to help limit neuronal injury and improve behavioral outcome. TBI involves a host of different biochemical events, including disruption of the cerebral vasculature and breakdown of the blood-brain barrier (BBB) that exacerbates secondary injuries. A better understanding of age-related mechanism(s) underlying brain injury will aid in establishing more effective treatment strategies aimed at improving restoration and preventing further neuronal loss. This review looks at studies that focus on modeling the adolescent population and highlights the importance of individualized aged therapeutics to TBI.

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Section: Age-at-injury Response To Preclinical Tbimentioning

confidence: 99%

Age-Dependent Responses Following Traumatic Brain Injury

Brickler¹,

Morton²,

Hazy³

et al. 2018

Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

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“…Brain ischemia is also characterized by a downregulation of GABAergic synaptic transmission, both at the pre-and postsynaptic levels [3,4], but the mechanisms involved are not fully understood. Recent studies showed a decrease in the interaction of GABA A receptors (GABA A R) with the scaffold protein gephyrin in cultured hippocampal neurons subjected to oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia, by a mechanism dependent on protein phosphatase activity [5].…”

Section: Introductionmentioning

confidence: 99%

Gephyrin Cleavage in In Vitro Brain Ischemia Decreases GABAA Receptor Clustering and Contributes to Neuronal Death

et al. 2015

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GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter in the central nervous system, and changes in GABAergic neurotransmission modulate the activity of neuronal networks. Gephyrin is a scaffold protein responsible for the traffic and synaptic anchoring of GABAA receptors (GABAAR); therefore, changes in gephyrin expression and oligomerization may affect the activity of GABAergic synapses. In this work, we investigated the changes in gephyrin protein levels during brain ischemia and in excitotoxic conditions, which may affect synaptic clustering of GABAAR. We found that gephyrin is cleaved by calpains following excitotoxic stimulation of hippocampal neurons with glutamate, as well as after intrahippocampal injection of kainate, giving rise to a stable cleavage product. Gephyrin cleavage was also observed in cultured hippocampal neurons subjected to transient oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia, and after transient middle cerebral artery occlusion (MCAO) in mice, a model of focal brain ischemia. Furthermore, a truncated form of gephyrin decreased the synaptic clustering of the protein, reduced the synaptic pool of GABAAR containing γ2 subunits and upregulated OGD-induced cell death in hippocampal cultures. Our results show that excitotoxicity and brain ischemia downregulate full-length gephyrin with a concomitant generation of truncated products, which affect synaptic clustering of GABAAR and cell death.

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“…This could explain the lower expression of AMPA GluA1 in rats given the 300 mg/kg dose, as a higher concentration of glutamate produced by the extract caused desensitization of the receptor in the adolescent age. GABA is implicated in many processes of neurogenesis, including neuronal proliferation, migration, differentiation, and preliminary circuit‐building, as well as the development during critical periods (Wu & Sun, 2015). In the mature CNS of the adult brain, GABA acts as an inhibitory neurotransmitter via activation of the fast hyperpolarizing GABA A receptors.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid GluA1 (AMPAGluA1) receptor subunit involves in learning and memory improvement following treatment withCentella asiaticaextract in adolescent rats

et al. 2018

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Introduction Centella asiatica is an herbal plant that contains phytochemicals that are widely believed to have positive effects on cognitive function. The adolescent stage is a critical development period for the maturation of brain processes that encompass changes in physical and psychological systems. However, the effect of C. asiatica has not been extensively studied in adolescents. The aim of this study was therefore to investigate the effects of a C. asiatica extract on the enhancement of learning and memory in adolescent rats.MethodsThe locomotor activity, learning, and memory were assessed by using open field test and water T‐maze test. This study also examined changes in neuronal cell morphology using cresyl violet and apoptosis staining. We also performed immunohistochemical study to analyse the expression of the glutamate AMPA receptor (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid) GluA1 subunit and the GABA receptor (γ‐Aminobutyric Acid) subtype GABAA α1 subunit in the hippocampus of the same animals.ResultsWe found no significant changes in locomotor activity (p > 0.05). The water T‐maze data showed that 30 mg/kg dose significantly (p < 0.05) improved learning, memory, and the memory consolidation phase but had no effect on reversal learning (p > 0.05). Histological data revealed no neuronal morphological changes. Immunohistochemical analysis revealed increased expression of the AMPA GluA1 receptor subunit but there was no effect on GABAA receptor α1 subunit expression in the CA1 and CA2 subregions of the hippocampus.ConclusionsThe C. asiatica extract therefore improved hippocampus‐dependent spatial learning and memory in a dose‐dependent manner in rats through the GluA1‐containing AMPA receptor in the CA1 and CA2 sub regions of the hippocampus.

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GABA receptors in brain development, function, and injury

Cited by 249 publications

References 90 publications

Age-Dependent Responses Following Traumatic Brain Injury

Age-Dependent Responses Following Traumatic Brain Injury

Gephyrin Cleavage in In Vitro Brain Ischemia Decreases GABAA Receptor Clustering and Contributes to Neuronal Death

Hippocampal amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid GluA1 (AMPAGluA1) receptor subunit involves in learning and memory improvement following treatment withCentella asiaticaextract in adolescent rats

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