GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity. / Walls, Anne B; Nilsen, Linn Hege; Eyjolfsson, Elvar M; Vestergaard, Henrik T; Hansen, Suzanne L; Schousboe, Arne; Sonnewald, Ursula; Waagepetersen, Helle S.

In: Journal of Neurochemistry, Vol. 115, No. 6, 2010, p. 1398–1408.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Walls, AB, Nilsen, LH, Eyjolfsson, EM, Vestergaard, HT, Hansen, SL, Schousboe, A, Sonnewald, U & Waagepetersen, HS 2010, 'GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity', Journal of Neurochemistry, vol. 115, no. 6, pp. 1398–1408. https://doi.org/10.1111/j.1471-4159.2010.07043.x

APA

Walls, A. B., Nilsen, L. H., Eyjolfsson, E. M., Vestergaard, H. T., Hansen, S. L., Schousboe, A., Sonnewald, U., & Waagepetersen, H. S. (2010). GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity. Journal of Neurochemistry, 115(6), 1398–1408. https://doi.org/10.1111/j.1471-4159.2010.07043.x

Vancouver

Walls AB, Nilsen LH, Eyjolfsson EM, Vestergaard HT, Hansen SL, Schousboe A et al. GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity. Journal of Neurochemistry. 2010;115(6):1398–1408. https://doi.org/10.1111/j.1471-4159.2010.07043.x

Author

Walls, Anne B ; Nilsen, Linn Hege ; Eyjolfsson, Elvar M ; Vestergaard, Henrik T ; Hansen, Suzanne L ; Schousboe, Arne ; Sonnewald, Ursula ; Waagepetersen, Helle S. / GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity. In: Journal of Neurochemistry. 2010 ; Vol. 115, No. 6. pp. 1398–1408.

Bibtex

@article{a3fb89b0f87411dfb6d2000ea68e967b,

title = "GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity",

abstract = "ABSTRACT: GABA is synthesized from glutamate by glutamate decarboxylase (GAD), which exists in two isoforms, that is, GAD65 and GAD67. In line with GAD65 being located in the GABAergic synapse, several studies have demonstrated that this isoform is important during sustained synaptic transmission. In contrast, the functional significance of GAD65 in the maintenance of GABA destined for extrasynaptic tonic inhibition is less well studied. Using GAD65-/- and wild type GAD65+/+ mice, this was examined employing the cortical wedge preparation, a model suitable for investigating extrasynaptic GABA(A) receptor activity. An impaired tonic inhibition in GAD65-/- mice was revealed demonstrating a significant role of GAD65 in the synthesis of GABA acting extrasynaptically. The correlation between an altered tonic inhibition and metabolic events as well as the functional and metabolic role of GABA synthesized by GAD65 was further investigated in vivo. Tonic inhibition and the demand for biosynthesis of GABA were augmented by injection of kainate into GAD65-/- and GAD65+/+ mice. Moreover, [1-(13) C]glucose and [1,2-(13) C]acetate were administered to study neuronal and astrocytic metabolism concomitantly. Subsequently, cortical and hippocampal extracts were analyzed by NMR spectroscopy and mass spectrometry, respectively. Although seizure activity was induced by kainate, neuronal hypometabolism was observed in GAD65+/+ mice. In contrast, kainate evoked hypermetabolism in GAD65-/- mice exhibiting deficiencies in tonic inhibition. These findings underline the importance of GAD65 for synthesis of GABA destined for extrasynaptic tonic inhibition, regulating epileptiform activity.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Walls, {Anne B} and Nilsen, {Linn Hege} and Eyjolfsson, {Elvar M} and Vestergaard, {Henrik T} and Hansen, {Suzanne L} and Arne Schousboe and Ursula Sonnewald and Waagepetersen, {Helle S}",

note = "{\textcopyright} 2010 The Authors. Journal of Neurochemistry {\textcopyright} 2010 International Society for Neurochemistry.",

year = "2010",

doi = "10.1111/j.1471-4159.2010.07043.x",

language = "English",

volume = "115",

pages = "1398–1408",

journal = "Journal of Neurochemistry",

issn = "0022-3042",

publisher = "Wiley-Blackwell",

number = "6",

}

RIS

TY - JOUR

T1 - GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity

AU - Walls, Anne B

AU - Nilsen, Linn Hege

AU - Eyjolfsson, Elvar M

AU - Vestergaard, Henrik T

AU - Hansen, Suzanne L

AU - Schousboe, Arne

AU - Sonnewald, Ursula

AU - Waagepetersen, Helle S

PY - 2010

Y1 - 2010

N2 - ABSTRACT: GABA is synthesized from glutamate by glutamate decarboxylase (GAD), which exists in two isoforms, that is, GAD65 and GAD67. In line with GAD65 being located in the GABAergic synapse, several studies have demonstrated that this isoform is important during sustained synaptic transmission. In contrast, the functional significance of GAD65 in the maintenance of GABA destined for extrasynaptic tonic inhibition is less well studied. Using GAD65-/- and wild type GAD65+/+ mice, this was examined employing the cortical wedge preparation, a model suitable for investigating extrasynaptic GABA(A) receptor activity. An impaired tonic inhibition in GAD65-/- mice was revealed demonstrating a significant role of GAD65 in the synthesis of GABA acting extrasynaptically. The correlation between an altered tonic inhibition and metabolic events as well as the functional and metabolic role of GABA synthesized by GAD65 was further investigated in vivo. Tonic inhibition and the demand for biosynthesis of GABA were augmented by injection of kainate into GAD65-/- and GAD65+/+ mice. Moreover, [1-(13) C]glucose and [1,2-(13) C]acetate were administered to study neuronal and astrocytic metabolism concomitantly. Subsequently, cortical and hippocampal extracts were analyzed by NMR spectroscopy and mass spectrometry, respectively. Although seizure activity was induced by kainate, neuronal hypometabolism was observed in GAD65+/+ mice. In contrast, kainate evoked hypermetabolism in GAD65-/- mice exhibiting deficiencies in tonic inhibition. These findings underline the importance of GAD65 for synthesis of GABA destined for extrasynaptic tonic inhibition, regulating epileptiform activity.

AB - ABSTRACT: GABA is synthesized from glutamate by glutamate decarboxylase (GAD), which exists in two isoforms, that is, GAD65 and GAD67. In line with GAD65 being located in the GABAergic synapse, several studies have demonstrated that this isoform is important during sustained synaptic transmission. In contrast, the functional significance of GAD65 in the maintenance of GABA destined for extrasynaptic tonic inhibition is less well studied. Using GAD65-/- and wild type GAD65+/+ mice, this was examined employing the cortical wedge preparation, a model suitable for investigating extrasynaptic GABA(A) receptor activity. An impaired tonic inhibition in GAD65-/- mice was revealed demonstrating a significant role of GAD65 in the synthesis of GABA acting extrasynaptically. The correlation between an altered tonic inhibition and metabolic events as well as the functional and metabolic role of GABA synthesized by GAD65 was further investigated in vivo. Tonic inhibition and the demand for biosynthesis of GABA were augmented by injection of kainate into GAD65-/- and GAD65+/+ mice. Moreover, [1-(13) C]glucose and [1,2-(13) C]acetate were administered to study neuronal and astrocytic metabolism concomitantly. Subsequently, cortical and hippocampal extracts were analyzed by NMR spectroscopy and mass spectrometry, respectively. Although seizure activity was induced by kainate, neuronal hypometabolism was observed in GAD65+/+ mice. In contrast, kainate evoked hypermetabolism in GAD65-/- mice exhibiting deficiencies in tonic inhibition. These findings underline the importance of GAD65 for synthesis of GABA destined for extrasynaptic tonic inhibition, regulating epileptiform activity.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1111/j.1471-4159.2010.07043.x

DO - 10.1111/j.1471-4159.2010.07043.x

M3 - Journal article

C2 - 21039523

VL - 115

SP - 1398

EP - 1408

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 6

ER -

ID: 23370766