Whole transcriptome analysis of the hippocampus: toward a molecular portrait of epileptogenesis

Abstract

BackgroundUncovering the molecular mechanisms involved in epileptogenesis is critical to better understand the physiopathology of epilepsies and to help develop new therapeutic strategies for this prevalent and severe neurological condition that affects millions of people worldwide.ResultsChanges in the transcriptome of hippocampal cells from rats subjected to the pilocarpine model of epilepsy were evaluated by microarrays covering 34,000 transcripts representing all annotated rat genes to date. Using such genome-wide approach, differential expression of nearly 1,400 genes was detected during the course of epileptogenesis, from the early events post status epilepticus (SE) to the onset of recurrent spontaneous seizures. Most of these genes are novel and displayed an up-regulation after SE. Noteworthy, a group of 128 genes was found consistently hyper-expressed throughout epileptogenesis, indicating stable modulation of the p38MAPK, Jak-STAT, PI3K, and mTOR signaling pathways. In particular, up-regulation of genes from the TGF-beta and IGF-1 signaling pathways, with opposite effects on neurogenesis, correlate with the physiopathological changes reported in humans.ConclusionsA consistent regulation of genes functioning in intracellular signal transduction regulating neurogenesis have been identified during epileptogenesis, some of which with parallel expression patterns reported in patients with epilepsy, strengthening the link between these processes and development of epilepsy. These findings reveal dynamic molecular changes occurring in the hippocampus that may serve as a starting point for designing alternative therapeutic strategies to prevent the development of epilepsy after acquired brain insults.

Role of Signal Transducer and Activator of Transcription-3 in Up-Regulation of GFAP After Epilepsy

“…After phosphorylation, STATs dimerize and translocate to the nucleus, where they bind specific regions to promote relative genes transcription [5]. Based on previous reports linking gliosis to STAT3 activation in glioblastoma [12] and the role of STAT3 in epileptogenesis [11], we here tested the hypothesis that p-STAT3 increases GFAP after epilepsy and that STAT3 activation contributes to reactive gliosismediated epileptogenesis. Our patients data demonstrate the up-regulation of p-STAT3 and GFAP.…”

“…For Zucai Xu and Tao Xue are equal to this article. example, STAT3 could be activated in the brain by specific triggers, such as cerebral ischemia, inflammatory stimulation, epilepsy [8][9][10][11]. Moreover, recent in vivo reports have revealed that STAT3 plays a central role in astrocyte proliferation and p-STAT3 regulates reactive astrogliosis (and GFAP expression) after CNS injury [12][13][14].…”

Epileptogenesis

“…These include involvement of proteolytic cascades (Gorter et al 2007), transforming growth factor b (TGF-b) and insulin-like growth factor 1 (IGF-1) signaling (Cacheaux et al 2009), p38MAPK, Jak-STAT, PI3K, mammalian target of rapamycin (mTOR) (Okamoto et al 2010), complement activation , and gene expression modulation related to glial oxidative stress and synaptic vesicle trafficking in epileptogenesis (Winden et al 2011). An obvious question related to changes in the transcriptome is: What controls gene expression?…”

Rapamycin suppresses PTZ-induced seizures at different developmental stages of zebrafish

“…Concerning the cellular and molecular processes that may be regulated by mTORC1 in the CNS, pharmacological modulation of the mTOR signaling pathway could be a promising alternative in different neurological disease therapies, such as in epilepsy treatment (Lipton and Sahin, 2014). In agreement, hyperactivation of mTOR signaling is evident in models of acute seizure (Zhang and Wong, 2012), status epilepticus (Okamoto et al, 2010), and epileptic patients (Berdichevsky et al, Fig. 1.…”