Gene Expression in Temporal Lobe Epilepsy is Consistent with Increased Release of Glutamate by Astrocytes

Abstract

Patients with temporal lobe epilepsy (TLE) often have a shrunken hippocampus that is known to be the location in which seizures originate. The role of the sclerotic hippocampus in the causation and maintenance of seizures in temporal lobe epilepsy (TLE) has remained incompletely understood despite extensive neuropathological investigations of this substrate. To gain new insights and develop new testable hypotheses on the role of sclerosis in the pathophysiology of TLE, the differential gene expression profile was studied. To this end, DNA microarray analysis was used to compare gene expression profiles in sclerotic and nonsclerotic hippocampi surgically removed from TLE patients. Sclerotic hippocampi had transcriptional signatures that were different from non-sclerotic hippocampi. The differentially expressed gene set in sclerotic hippocampi revealed changes in several molecular signaling pathways, which included the increased expression of genes associated with astrocyte structure (glial fibrillary acidic protein, ezrin-moesin-radixin, palladin), calcium regulation (S100 calcium binding protein beta, chemokine (C-X-C motif) receptor 4) and blood-brain barrier function (Aquaaporin 4, Chemokine (C-C-motif) ligand 2, Chemokine (C-C-motif) ligand 3, Plectin 1, intermediate filament binding protein 55kDa) and inflammatory responses. Immunohistochemical localization studies show that there is altered distribution of the gene-associated proteins in astrocytes from sclerotic foci compared with nonsclerotic foci. It is hypothesized that the astrocytes in sclerotic tissue have activated molecular pathways that could lead to enhanced release of glutamate by these cells. Such glutamate release may excite surrounding neurons and elicit seizure activity.

Stress-Dependent Changes in the CacyBP/SIP Interacting Protein S100A6 in the Mouse Brain

“…In all these cases, as well as in normal aging, S100A6 is up-regulated. Increases in the levels of S100A6 mRNA have also been demonstrated in epilepsy [13, 14] and following traumatic brain injury [15]. Up-regulation of this protein has been observed in a rat model of epilepsy that is induced by amygdalar stimulation.…”

Why mesial temporal lobe epilepsy with hippocampal sclerosis is progressive: Uncontrolled inflammation drives disease progression?

“…Reactive astrocytes are associated with increased expression of many proteins, including a variety of cytokines such as TGF-β, TNF-α, and interleukins 1, 4, 6, and 10 [71,72], as well as the proinflammatory proteins COX-2 and CXCR-4 [73]. Accumulating evidence supports the role of IL-1 in reducing seizure threshold and epileptogenesis in the pilocarpine SE model of epilepsy [44].…”

L-Glutamate Enhances Barrier and Antioxidative Functions in Intestinal Porcine Epithelial Cells,

“…Furthermore, Glu can activate chemical sensors in the gastrointestinal tract, leading to the generation of serotonin (a neurotransmitter) by enteroendocrine cells (14). Emerging evidence also shows that Glu plays important roles in intestinal nutrition (15), cell signaling, the modulation of gene expression (16), anti-inflammatory responses (17,18), and immunity (19,20). Transport of Glu primarily by the excitatory amino acid transporter 3 (EAAT3) is the first step in the utilization of this amino acid by enterocytes (21,22).…”