Dorsal bed nucleus of stria terminalis in depressed and nondepressed temporal lobe epilepsy patients.

Objective: Temporal lobe epilepsy (TLE) and depression are common comorbid disorders whose underlying shared neural network has yet to be determined. Although animal studies demonstrate a role for the dorsal bed nucleus of the stria terminalis (dBNST) in both seizures and depression, and human clinical studies demonstrate a therapeutic effect of stimulating this region on treatment-resistant depression, the role of the dBNST in depressed and nondepressed TLE patients is still unclear. Here, we tested the hypothesis that this structure is morphologically abnormal in these epilepsy patients, with an increased abnormality in TLE patients with comorbid depression.

Small loci of astroglial glutamine synthetase deficiency in the postnatal brain cause epileptic seizures and impaired functional connectivity.

Objective: The astroglial enzyme glutamine synthetase (GS) is deficient in small loci in the brain in adult patients with different types of focal epilepsy; however, the role of this deficiency in the pathogenesis of epilepsy has been difficult to assess due to a lack of sufficiently sensitive and specific animal models. The aim of this study was to develop an in vivo approach for precise and specific deletions of the GS gene in the postnatal brain.

Methods: We stereotaxically injected various adeno-associated virus (AAV)-Cre recombinase constructs into the hippocampal formation and neocortex in 22-70-week-old GS mice to knock out the GS gene in a specific and focal manner.

Increased branched-chain amino acids at baseline and hours before a spontaneous seizure in the human epileptic brain.

The objective of this study was to monitor the extracellular brain chemistry dynamics at baseline and in relation to spontaneous seizures in human patients with refractory epilepsy. Thirty patients with drug-resistant focal epilepsy underwent intracranial electroencephalography and concurrent brain microdialysis for up to 8 continuous days. Extracellular brain glutamate, glutamine, and the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine were quantified in the dialysis samples by liquid chromatography-tandem mass spectrometry.

Astroglial Glutamine Synthetase and the Pathogenesis of Mesial Temporal Lobe Epilepsy.

The enzyme glutamine synthetase (GS), also referred to as glutamate ammonia ligase, is abundant in astrocytes and catalyzes the conversion of ammonia and glutamate to glutamine. Deficiency or dysfunction of astrocytic GS in discrete brain regions have been associated with several types of epilepsy, including medically-intractable mesial temporal lobe epilepsy (MTLE), neocortical epilepsies, and glioblastoma-associated epilepsy. Moreover, experimental inhibition or deletion of GS in the entorhinal-hippocampal territory of laboratory animals causes an MTLE-like syndrome characterized by spontaneous, recurrent hippocampal-onset seizures, loss of hippocampal neurons, and in some cases comorbid depressive-like features.

Network-Related Changes in Neurotransmitters and Seizure Propagation During Rodent Epileptogenesis.

Objective: To test the hypothesis that glutamate and GABA are linked to the formation of epilepsy networks and the triggering of spontaneous seizures, we examined seizure initiation/propagation characteristics and neurotransmitter levels during epileptogenesis in a translationally relevant rodent model of mesial temporal lobe epilepsy.

Methods: The glutamine synthetase (GS) inhibitor methionine sulfoximine was infused into one of the hippocampi in laboratory rats to create a seizure focus. Long-term video-intracranial EEG recordings and brain microdialysis combined with mass spectrometry were used to examine seizure initiation, seizure propagation, and extracellular brain levels of glutamate and GABA.

Circadian-Like Rhythmicity of Extracellular Brain Glutamate in Epilepsy.

Seizures often exhibit striking circadian-like (~24-h) rhythms. While chronotherapy has shown promise in treating epilepsy, it is not widely used, in part because the patterns of seizure rhythmicity vary considerably among patients and types of epilepsy. A better understanding of the mechanisms underlying rhythmicity in epilepsy could be expected to result in more effective approaches which can be tailored to each individual patient.

Oral glutamine supplementation increases seizure severity in a rodent model of mesial temporal lobe epilepsy.

Glutamine synthetase (GS) is the only enzyme known to synthesize significant amounts of glutamine in mammals, and loss of GS in the hippocampus has been implicated in the pathophysiology of medication refractory mesial temporal lobe epilepsy (MTLE). Moreover, loss-of-function mutations of the GS gene causes severe epileptic encephalopathy, and supplementation with glutamine has been shown to normalize EEG and possibly improve the outcome in these patients. Here we examined whether oral glutamine supplementation is an effective treatment for MTLE by assessing the frequency and severity of seizures after supplementation in a translationally relevant model of the disease.

Branched-Chain Amino Acids and Seizures: A Systematic Review of the Literature.

Background: Up to 40% of patients with epilepsy experience seizures despite treatment with antiepileptic drugs; however, branched-chain amino acid (BCAA) supplementation has shown promise in treating refractory epilepsy.

Objectives: The purpose of this systematic review was to evaluate all published studies that investigated the effects of BCAAs on seizures, emphasizing therapeutic efficacy and possible underlying mechanisms.

Methods: On 31 January, 2017, the following databases were searched for relevant studies: MEDLINE (OvidSP), EMBASE (OvidSP), Scopus (Elsevier), the Cochrane Library, and the unindexed material in PubMed (National Library of Medicine/National Institutes of Health).

Effects of Branched-Chain Amino Acid Supplementation on Spontaneous Seizures and Neuronal Viability in a Model of Mesial Temporal Lobe Epilepsy.

Background: The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine have recently emerged as a potential novel treatment for medically refractory epilepsy. Blood-derived BCAAs can readily enter the brain, where they contribute to glutamate biosynthesis and may either suppress or trigger acute seizures. However, the effects of BCAAs on chronic (ie, spontaneous recurrent) seizures and epilepsy-associated neuron loss are incompletely understood.

Network evolution in mesial temporal lobe epilepsy revealed by diffusion tensor imaging.

Objective: The objective of the present study is to identify novel, time-indexed imaging biomarkers of epileptogenesis in mesial temporal lobe epilepsy (MTLE).

Methods: We used high-resolution brain diffusion tensor imaging (DTI) of the translationally relevant methionine sulfoximine (MSO) brain infusion model of MTLE. MSO inhibits astroglial glutamine synthetase, which is deficient in the epileptogenic hippocampal formation of patients with MTLE.

The Glutamate-Glutamine Cycle in Epilepsy.

Epilepsy is a complex, multifactorial disease characterized by spontaneous recurrent seizures and an increased incidence of comorbid conditions such as anxiety, depression, cognitive dysfunction, and sudden unexpected death. About 70 million people worldwide are estimated to suffer from epilepsy, and up to one-third of all people with epilepsy are expected to be refractory to current medications. Development of more effective and specific antiepileptic interventions is therefore requisite.

Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition.

Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis).

Imaging synaptic density in the living human brain.

Chemical synapses are the predominant neuron-to-neuron contact in the central nervous system. Presynaptic boutons of neurons contain hundreds of vesicles filled with neurotransmitters, the diffusible signaling chemicals. Changes in the number of synapses are associated with numerous brain disorders, including Alzheimer's disease and epilepsy.

Effects of site-specific infusions of methionine sulfoximine on the temporal progression of seizures in a rat model of mesial temporal lobe epilepsy.

Glutamine synthetase (GS) in astrocytes is critical for metabolism of glutamate and ammonia in the brain, and perturbations in the anatomical distribution and activity of the enzyme are likely to adversely affect synaptic transmission. GS is deficient in discrete regions of the hippocampal formation in patients with mesial temporal lobe epilepsy (MTLE), a disorder characterized by brain glutamate excess and recurrent seizures. To investigate the role of site-specific inhibition of GS in MTLE, we chronically infused the GS inhibitor methionine sulfoximine (MSO) into one of the following areas of adult laboratory rats: (1) the angular bundle, n=6; (2) the deep entorhinal cortex (EC), n=7; (3) the stratum lacunosum-moleculare of CA1, n=7; (4) the molecular layer of the subiculum, n=10; (5) the hilus of the dentate gyrus, n=6; and (6) the lateral ventricle, n=6.

5-aminovaleric acid suppresses the development of severe seizures in the methionine sulfoximine model of mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of drug-resistant, localization-related epilepsies in humans. One potential therapeutic target is the brain glutamine-glutamate-GABA metabolic pathway, which is perturbed in patients with MTLE. Loss of glutamine synthetase (GS) in astrocytes may be critically involved in this perturbation, which can be modeled by infusing the GS inhibitor methionine sulfoximine (MSO) into the entorhinal-hippocampal area in rats.