A pathway diagram developed using the Ingenuity Pathways Analysis and Knowledge Base in which all genes changed by more than 1.5 fold were queried. This diagram shows one of the relational networks in which all up-regulated genes (green) were those related to astrocyte structure or function. This network is very significant with a score of 40, which means that the association by chance alone is less than 99.99%. Those genes with a significant increase in fold change in our study are shaded green, while those with a decrease are shaded in red. In the diagram, the vertical diamond shape represents an enzyme, a horizontal diamond is a peptidase, downward pointing triangle is a kinase, horizontal rectangle is a nuclear receptor, the oval a transcription factor, and the round other genes. Lines with arrow head = acts on; line with short perpendicular line at end = inhibits; plain line = binds only.
Abbreviations of gene names: ADAMTS3, Disintegrin-like and metalloprotease with thrombospondin type 1 motif, 3; AHNAK, AHNAK nucleoprotein (desmoyokin); CAPN2, Calpain 2; CAPN3, Calpain 3; CAST, Calpastatin; CD44, CD44 antigen (homing function and Indian blood group system); CRYAB, Crystallin α B; CSPG2, Chondroitin sulfate proteoglycan 2 (Versican); CSPG3, Chondroitin sulfate proteoglycan 3 (neurocan); FBXW7, F-box and WD-40 domain protein 7; FGF1, Fibroblast growth factor 1 (acidic); FGFR2, Fibroblast growth factor receptor 2; G3PB2, Ras-GTPase activating protein SH3 domain-binding protein 2; GFAP, Glial fibrillary acidic protein; KIAA0992, Palladin; MET, Met proto-oncogene (hepatocyte growth factor receptor); MSN, Moesin; NET1, Neuroepithelial cell transforming gene 1; NFKBIA, Nuclear factor kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; PCTK3, PCTAIRE protein kinase 3; PDE8A, Phosphodiesterase 8A; PLEC1, Plectin 1, intermediate filament binding protein 500kDa; PPFIA1, Protein tyrosine phosphatase, receptor type f, interacting protein (liprin), α 1; PSEN1, Presenilin 1 (Alzheimer disease 3); PTGS2, Prostaglandin-endoperoxide synthase 2 (G/H synthase and cyclooxygenase); RDX, Radixin; S100A6, S100 calcium binding protein A6 (calcyclin); S100B, S100 calcium binding protein, β (neural); TNC, Tenascin-C; TTN, Titin; VCAM1, Vascular cell adhesion molecule 1; VIL2, Villin 2 (ezrin); YWHAZ, Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta.

Hypothesized molecular pathways for glutamate release from astrocytes in sclerotic hippocampi. This diagram is constructed on the basis of molecules produced by genes whose expression was found to increase (outlined in red) in this study and those reported in other studies (outlined in blue; also see text) of human TLE. The figure also shows that many of the pathways could be activated through known initial precipitating factors of TLE. Abbreviations: CCL2, CCL3, and CCL4, CC family chemokines; CD44, CD44 antigen (homing function and Indian blood group system); CX3CL1, fractalkine; CXCR4, α-chemokine receptor; COX-2, cyclooxygenase-2; EP1,3, calcium mobilizing receptors for PGE2; ERK1,2, extracellular signal-related kinases; HA, hyaluronan; IL-1β, interleukin-1β; HSV, herpes simplex virus; HHV6, human herpes virus 6; IL-1R, interleukin 1 receptor; PGE2, prostaglandin E₂; SDF1, stromal derived factor 1, also known as CXCL12; TLR, Toll-like receptor; TNFR, tumor necrosis factor receptor; TNF-α, tumor necrosis factor α.

The comparison of the gene expression patterns in 20 hippocampi from patients with TLE. The dendrogram was obtained by unsupervised hierarchical cluster analysis using Gene Spring software. The analysis included all genes expressed in a microarray analysis using the Affymetrix GeneChip U133A. It shows a primary branching pattern, which separates the sclerotic MTLE (dark green) hippocampi as one cluster. The PTLE (blue) and MaTLE (Red), both being non-sclerotic hippocampi, form a separate group. On the dendrogram, each horizontal color bar denotes the intensity of expression of a particular gene relative to the mean expression value of all samples. The color codes are shown in the color bar where green represents transcript levels below the median and red represents transcript levels above. Yellow is at median. The more intense the color, the greater the level of trust it represents. MTLE = mesial temporal lobe epilepsy; MaTLE = mass associated temporal lobe epilepsy; PTLE = paradoxical temporal lobe epilepsy.

This figure shows photomicrographs of the localization in area CA1 pyramidal layer of non-sclerotic (non-MTLE, A, C. E. G, I) and sclerotic (MTLE, B, D, F, H, J) hippocampi of some proteins whose genes showed changes in expression in this study. A & B show the immunolocalization of AQP4 (Aquaporin 4). Note the reduction in immunoreactivity in astrocytic foot processes around blood vessels in MTLE and increase in astrocytic processes throughout the pyramidal layer. C & D show reduction in DMD (Dystrophin) around blood vessels in MTLE. E & F show localization of CD44 (CD44 antigen). In the non-sclerotic hippocampus (E) immunoreactivity is seen on fiber-like processes (arrow) extending into the pyramidal layer from the stratum oriens. Scattered among these fibers are CD44 positive astrocyte cell bodies (not shown). In MTLE, many more astrocytes are immunoreactive and form a dense network throughout the region with more intense staining in perivascular foot processes (arrow in F). G & H show PLEC1 (Pectin 1, intermediate filament binding protein 500kDa) immunoreactivity, which is increased in expression in astrocyte cell bodies and perivascular foot processes (arrow). I & J show an increase in CXCR4 (Chemokine (C-X-C motif) receptor 4) expression on microglia in the sclerotic hippocampus (arrow). CXCR4 is increased on a small proportion of astrocytes as well.