Knockout of GAD65 has Major Impact on Synaptic GABA Synthesized from Astrocyte-Derived Glutamine

Walls, Anne B.; Eyjolfsson, Elvar M.; Smeland, Olav B.; Nilsen, Linn Hege; Schousboe, Inger; Schousboe, Arne; Sonnewald, Ursula; Waagepetersen, Helle S.

doi:10.1038/jcbfm.2010.115

Cited by 73 publications

(66 citation statements)

References 42 publications

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“…In line with these findings, we have previously reported that the synthesis of neurotransmitter GABA is altered during chronic HE (Leke et al, 2011a), albeit no change was observed in the expression of GAD65, which is the GAD isoform closely associated with the biosynthesis of GABA in the vesicular neurotransmitter pool Waagepetersen et al, 1999Waagepetersen et al, , 2001Walls et al, 2011). Considering that glutamine is important in the restoration of GABA pools and that synthesis of this amino acid is disturbed during HE, it is possible that during this neurologic disorder the expression of the glutamine transporter isoforms might be altered which would consequently affect the function of the glutamate/GABA-glutamine cycle and thus likely contribute to the observed disturbance of GABA neurotransmitter synthesis (for further discussion, see Walls et al, 2015).…”

Section: Discussionsupporting

confidence: 70%

“…In this context it is of interest that using bileduct ligated rats (BDL), an experimental model of chronic HE, it has been demonstrated that the biosynthetic pathway for GABA was altered to occur preferentially via the tricarboxylic acid (TCA) cycle relative to the direct decarboxylation of glutamate not involving the TCA cycle (Leke et al, 2011a). However, no differences in the gene expression were found for the glutamate decarboxylase (GAD) enzyme isoforms GAD65 and GAD67 , which have different roles in the two GABA biosynthetic pathways mentioned earlier (Waagepetersen et al, 1999(Waagepetersen et al, , 2001Walls et al, 2011). Therefore, it can be hypothesized that glutamine transfer between astrocytes and neurons may be altered leading to changes in the biosynthesis of neurotransmitter GABA.…”

Section: Introductionmentioning

confidence: 87%

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Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Leke

Escobar

Rao

et al. 2015

Neurochemistry International

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Rama Rao, Kakulavarapu V.; Silveira, Themis Reverbel; Norenberg, Michael D.; and Schousboe, Arne, "Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy" (2015 Keywords:Chronic hepatic encephalopathy Glutamine transporters Glutamine GABA A B S T R A C THepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs due to acute and chronic liver diseases, the hallmark of which is the increased levels of ammonia and subsequent alterations in glutamine synthesis, i.e. conditions associated with the pathophysiology of HE. Under physiological conditions, glutamine is fundamental for replenishment of the neurotransmitter pools of glutamate and GABA. The different isoforms of glutamine transporters play an important role in the transfer of this amino acid between astrocytes and neurons. A disturbance in the GABA biosynthetic pathways has been described in bile duct ligated (BDL) rats, a well characterized model of chronic HE. Considering that glutamine is important for GABA biosynthesis, altered glutamine transport and the subsequent glutamate/GABA-glutamine cycle efficacy might influence these pathways. Given this potential outcome, the aim of the present study was to investigate whether the expression of the glutamine transporters SAT1, SAT2, SN1 and SN2 would be affected in chronic HE. We verified that mRNA expression of the neuronal glutamine transporters SAT1 and SAT2 was found unaltered in the cerebral cortex of BDL rats. Similarly, no changes were found in the mRNA level for the astrocytic transporter SN1, whereas the gene expression of SN2 was increased by two-fold in animals with chronic HE. However, SN2 protein immuno-reactivity did not correspond with the increase in gene transcription since it remained unaltered. These data indicate that the expression of the glutamine transporter isoforms is unchanged during chronic HE, and thus likely not to participate in the pathological mechanisms related to the imbalance in the GABAergic neurotransmitter system observed in this neurologic condition.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 87%

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Leke

Escobar

Rao

et al. 2015

Neurochemistry International

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“…[23][24][25][26] In the present study, the level of cortical Glu (13.8 mmol/g), GABA (2.4 mmol/g), NAA (8.1 mmol/g), and Ins (6.5 mmol/g) is slightly higher than in vivo values, but significantly lower than ex vivo values. 27 Although absolute levels of metabolites are reported to vary across different studies, there seems to be a specific pattern for variation in the level of neurometabolites across the brain. Our data indicate that Glu level decreases in the following order: the cerebral cortex4hippocampus4striatumBthalamus-hypothalamus4 cerebellum.…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic and GABAergic TCA Cycle and Neurotransmitter Cycling Fluxes in Different Regions of Mouse Brain

Tiwari

Ambadipudi

Patel

2013

J Cereb Blood Flow Metab

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The 13 C nuclear magnetic resonance (NMR) studies together with the infusion of 13 C-labeled substrates in rats and humans have provided important insight into brain energy metabolism. In the present study, we have extended a three-compartment metabolic model in mouse to investigate glutamatergic and GABAergic tricarboxylic acid (TCA) cycle and neurotransmitter cycle fluxes across different regions of the brain. ]glucose were analyzed using a threecompartment metabolic model to estimate the rates of the TCA cycle and neurotransmitter cycle associated with glutamatergic and GABAergic neurons. The glutamatergic TCA cycle rate was found to be highest in the cerebral cortex (0.91 ± 0.05 mmol/g per minute) and least in the hippocampal region (0.64±0.07 mmol/g per minute) of the mouse brain. In contrast, the GABAergic TCA cycle flux was found to be highest in the thalamus-hypothalamus (0.28±0.01 mmol/g per minute) and least in the cerebral cortex (0.24 ± 0.02 mmol/g per minute). These findings indicate that the energetics of excitatory and inhibitory function is distinct across the mouse brain.

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“…While GAD67 is expressed throughout the cytosol, GAD65 is the dominant presynaptic isoform, which is directly associated to presynaptic vesicles and therefore seems to be important for their filling. 106,155,156 This filling process, however, requires activity of a vacuolar H þ -ATPase that provides the electrical (DC) and chemical (DpH) components of the driving force for the vesicular inhibitory amino-acid transporter. 147,157 After release to the synaptic cleft, re-uptake of GABA occurs via Na þ -/Cl À -dependent GABA transporter 1 in the presynaptic terminal or via GAT-3 in processes of astrocytes that enwrap the synapse.…”

Section: Energy Utilization Of Fast-spiking Behavior and Synaptic Inhmentioning

confidence: 99%

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

Kann

Papageorgiou

Draguhn

2014

J Cereb Blood Flow Metab

226

235

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Gamma oscillations (B30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency ('fast-spiking') and synchronize the activity of numerous pyramidal cells by rhythmic inhibition ('clockwork'). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and g-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited ('interneuron energy hypothesis'). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.

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Knockout of GAD65 has Major Impact on Synaptic GABA Synthesized from Astrocyte-Derived Glutamine

Cited by 73 publications

References 42 publications

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Glutamatergic and GABAergic TCA Cycle and Neurotransmitter Cycling Fluxes in Different Regions of Mouse Brain

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

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