Glutamate and GABA synthesis, release, transport and metabolism as targets for seizure control

Rowley, Nicole M.; Madsen, Karsten K.; Schousboe, Arne; White, H. Steve

doi:10.1016/j.neuint.2012.02.013

Cited by 152 publications

(126 citation statements)

References 177 publications

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“…GABA is degraded by the enzyme GABAtransaminase (GABA-T/ABAT) and converted to glutamate and succinic semialdehyde (SSA). The latter is used by the enzyme SSADH/ALDH5A1 to generate succinate for the Krebs cycle (Rowley et al, 2012). (B) During early development, GABA A R-mediated signaling is depolarizing due to high expression of NKCC1 and high intracellular chloride concentration.…”

Section: Known Consequences Of Genetic Variation In the Gabaergic Systemmentioning

confidence: 99%

“…Tiagabine is a GABA reuptake inhibitor that specifically blocks the GABA transporter GAT1 (Madsen et al, 2010). Vigabatrin is an irreversible inhibitory of GABA-T, thus blocking GABA catabolism (Rowley et al, 2012). Immature GABA A receptor signaling can be targeted with bumetanide, an inhibitor of NKCC1, which decreases the intracellular chloride concentration.…”

Section: Known Consequences Of Genetic Variation In the Gabaergic Systemmentioning

confidence: 99%

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The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

Braat

Kooy

2015

Neuron

256

214

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Intellectual disability, autism spectrum disorder, and epilepsy are prime examples of neurodevelopmental disorders that collectively affect a significant percentage of the world population. Recent technological breakthroughs allowed the elucidation of the genetic causes of many of these disorders. As neurodevelopmental disorders are genetically heterogeneous, the development of rational therapy is extremely challenging. Fortunately, many causative genes are interconnected and cluster in specific cellular pathways. Targeting a common node in such a network would allow us to interfere with a series of related neurodevelopmental disorders at once. Here, we argue that the GABAergic system is disturbed in many neurodevelopmental disorders, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and is a key candidate target for therapeutic intervention. Many drugs that modulate the GABAergic system have already been tested in animal models with encouraging outcomes and are readily available for clinical trials.

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Section: Known Consequences Of Genetic Variation In the Gabaergic Systemmentioning

confidence: 99%

Section: Known Consequences Of Genetic Variation In the Gabaergic Systemmentioning

confidence: 99%

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

Braat

Kooy

2015

Neuron

256

214

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“…Alterations in amino acid homeostasis in the central nervous system are crucial for epileptogenesis (9). Certain amino acids such as tyrosine are biogenic amine precursors;…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Efficacy of the Ketogenic Diet for the Treatment of Refractory Childhood Epilepsy: Cerebrospinal Fluid Neurotransmitters and Amino Acid Levels

Sariego-Jamardo¹,

García‐Cazorla²,

Artuch³

et al. 2015

Pediatric Neurology

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“…However, this is an oversimplification of mitochondrial physiology. In addition to carrying out ATP synthesis through oxidative phosphorylation, mitochondria are also important for Ca 2+ signaling (Brini et al, 2014;Nicholls, 2005;Duchen, 2000;Clapham, 2007), cell death (Tait and Green, 2013;Duchen, 2000), steroid synthesis (Miller, 2011), reactive oxygen species (ROS) production and sequestration (Zorov et al, 2014;Hamanaka and Chandel, 2010;Shadel and Horvath, 2015;Accardi et al, 2014), and neurotransmitter synthesis and inactivation (Rowley et al, 2012;Bak et al, 2005;Waagepetersen et al, 2000). Given the importance of processes, such as ATP production, Ca 2+ transients, neurotransmitter metabolism and ROS signaling, in synaptic transmission it is not surprising that recent work has illustrated that perturbations in mitochondrial physiology exert profound effects on neuronal development and function.…”

Section: Introductionmentioning

confidence: 99%