Astroglial Glutamine Synthetase and the Pathogenesis of Mesial Temporal Lobe Epilepsy

Abstract

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. The goal of this review is to summarize and discuss the possible roles of astroglial GS in the pathogenesis of epilepsy.

Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina

“…Indeed, in photoreceptor cells death (related to inherited photoreceptor degeneration, retinal light injury, or retinal detachment), Müller cells display a drop in their GS expression and glutamine level [ 60 , 61 , 62 ]. Similarly, a decline in GS expression and activity was also observed under ischemic, inflammatory, and traumatic conditions or in glaucoma [ 7 , 63 , 64 , 65 ]. These observations are in accordance with experimental data using pharmacological inhibitor of the GS activity in the retina.…”

“…Indeed, in the tripartite glutamatergic synapse (photoreceptor, bipolar and Müller cells), Müller cells regulate the glutamate/glutamine metabolic cycle in order to control glutamate level. This cycle aims to recapture glutamate from the synaptic cleft, thus avoiding excitotoxicity [ 6 , 7 ] and providing glutamine to replenish neurotransmitter pools in neurons. Glutamate internalization into Müller cells is supported by high-affinity Na+-dependent transporters (EAAT1 or GLAST).…”

Altered plasma glutamate and glutamine levels in patients with drug-resistant and drug-responsive symptomatic focal epilepsy

“…Changes in extracellular glutamate concentrations are considered as an output of neuron-astrocyte unit activity. 15 , 16 Both neurons and astrocytes can release and take up glutamate, and both cell types are involved in regulating extracellular amounts of glutamate. 17 , 18 Excitatory amino acid transporters (EAATs) localized in astrocytes and neurons catalyze glutamate metabolism and diminish extracellular glutamate.…”

“… 2 Reduced GS protein expression and activity were confirmed in the hippocampus of temporal lobe epilepsy patients with hippocampal sclerosis relative to patients without sclerosis and in non-epileptic control subjects. 16 Moreover, GS deficiency has been shown to be more pronounced in the hippocampus with astroglial proliferation. 20 Glutamine synthetase deficiency inhibits the astrocytic glutamate-glutamine cycle and results in a higher load of extracellular glutamate.…”

Structure Of Eukaryotic Type III Glutamine Synthetase Lacking Ring-Ring Quaternary Contacts

“…Similarly, drug screening trials against tuberculosis GS proteins are undergoing [2][3][4] . Human GS is also being considered as a potential drug target to regulate several neurological disorders 5,6 .…”