Biology Reference
In-Depth Information
DNA arrays are commonly used for monitoring expression levels of thousands of genes
simultaneously. In our studies, we hypothesize that epileptic hippocampi have transcriptional
changes that are different from the transcriptomes produced in non-epileptic hippocampi
where we are predicting that some of the same genes that are expressed after the induction of
LTP are also expressed following epileptic seizures.
In one recent study using DAN microarrays, experiments were conducted to clarify the
role of various neurotrophic factors in the pilocarpine model of seizures. It was found [52]
that 4 hours following pilocarpine-induced seizures, expression of nerve growth factor
(NGF), brain derived neurotrophic factor (BDNF), heparin-binding epidermal growth factor-
like growth factor, (HB-EGF), and fibroblast growth factor (FGF) increased in the mice
manifesting tonic-clonic convulsions, but not in mice without seizures. These results suggest
that brain damage in the mice having tonic-clonic seizures is accompanied by neurogenesis,
which may be regulated through changes in expression of neurotrophic factors.
The regulation of gene expression by NMDA receptor activation may also be an
important mechanism for plasticity in epileptogenesis. Previous studies showed that
pretreatment of rodents with NMDA receptor antagonists prevented epileptogenesis in a
kindling model [53, 54]. As a recent follow up, the roles of NR2A and NR2B-containing
NMDA receptors in activity-dependent BDNF gene expression were examined in limbic
epileptogenesis [55]. Here it was found that selectively blocking NR2A-containing NMDA
receptors impaired epileptogenesis and the development of mossy fiber sprouting in the
kindling and pilocarpine rat models of limbic epilepsy, whereas inhibiting NR2B-containing
NMDA receptors had no effects in epileptogenesis and mossy fiber sprouting.
Another important finding is that neurotrophins themselves appear regulated by
neurotrophin levels in epilepsy models. In one new study, hippocampal kindling resulted in a
significant increase in levels of BDNF both in cytochrome C (control) infused and
neurotrophin-3 (NT-3) infused kindled rats [56]. However, NT-3 infusion significantly
reduced BDNF levels in both kindled and non-kindled hippocampi compared to their
cytochrome C infused counterparts. These results demonstrate that modulation of BDNF by
NT-3 occurs in naïve and kindled adult rat hippocampus.
C
ONCLUSION
One interesting aspect of these recent studies, is that the results provide a potential
process and therapeutic target for blocking the progression of the epileptic state. In other
words, to be able to block the recruitment of more neurons from falling into an abnormal
discharge pattern, may hold clinical value for epileptic patients. Future research that involves
specific treatments directed at signaling cascades that trigger gene expression or which
modulate the synthesis of certain gene products, may be in order. In fact, the idea of a so-
called “afterseizure” drug intervention has been entertained that would interfere with the
expression of particular genes and prevent modifications that might lead to enhanced
excitability.
The development of these interventions, however, will require more fundamental
research using techniques such as gene arrays and other molecular methods for expanding our
basic knowledge of seizure-induced gene expression. Importantly, it is essential that we
