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Molecular mechanisms of epilepsy

Epilepsy is a chronic neurological disorder, affecting 1-3% of our population. Current anti-epileptic drugs are ineffective in more than 30% of patients with the most common type of the disease.
Molecular mechanisms of epilepsy
Temporal lobe epilepsy is the most common type of the disease in adults. Multiple evidence points to malfunction of synapses (aberrant synaptic plasticity) as the reason behind epilepsy. Understanding the molecular mechanisms underlying this pathology is very important for more efficient treatment.

Inactivation of transcription regulator serum response factor (SRF) in a mouse model caused deficiency in synaptic plasticity and learning. SRF is also involved in axonal outgrowth and guidance. The EU-funded 'SRF target genes in epilepsy' (EPITARGENE) project was to identify genes regulated by SRF in epilepsy.

For the project experiments, researchers obtained an inducible, forebrain-specific SRF knockout line of mice (SRF KO). This mice lack SRF protein in the brain during adulthood.

Microarray expression analysis revealed that in basic conditions (saline treated animals) SRF KOs do not display any significantly down-regulated transcripts. However, after aberration of synaptic plasticity with kainic acid, 260 genes showed increased expression in control animals and were significantly down-regulated in SRF KOs.

Among those genes, researchers experimentally identified potential plasticity related gene lipocalin 2 (Lcn2). This is a small, secreted protein originally identified as a protein associated with plasticity related protease MMP-9.

The evaluation of the role of Lcn2 in structural synaptic plasticity showed that an increased level of Lcn2 may exert rapid effects on the dendritic spine morphology. Lcn2 caused elongation, thinning and a decrease in the proportion of mature spines, and possibly lowered the hyper excitability of the network.

Results of the project will improve our understanding of the pathogenesis of epilepsy. It will influence the development of new therapeutic opportunities by targeting aberrant plasticity-related SRF effectors.

Related information

Keywords

Epilepsy, temporal lobe epilepsy, synaptic plasticity, serum response factor, lipocalin 2, hyper excitability
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