Abstract
The Brain-Derived Neurotrophic Factor is one of the most important trophic proteins in the brain. The role of this growth factor in neuronal plasticity, in health and disease, has been extensively studied. However, mechanisms of epigenetic regulation of Bdnf gene expression in epilepsy are still elusive. In our previous work, using a rat model of neuronal activation upon kainate-induced seizures, we observed a repositioning of Bdnf alleles from the nuclear periphery towards the nuclear center. This change of Bdnf intranuclear position was associated with transcriptional gene activity. In the present study, using the same neuronal activation model, we analyzed the relation between the percentage of the Bdnf allele at the nuclear periphery and clinical and morphological traits of epilepsy. We observed that the decrease of the percentage of the Bdnf allele at the nuclear periphery correlates with stronger mossy fiber sprouting-an aberrant form of excitatory circuits formation. Moreover, using in vitro hippocampal cultures we showed that Bdnf repositioning is a consequence of transcriptional activity. Inhibition of RNA polymerase II activity in primary cultured neurons with Actinomycin D completely blocked Bdnf gene transcription and repositioning occurring after neuronal excitation. Interestingly, we observed that histone deacetylases inhibition with Trichostatin A induced a slight increase of Bdnf gene transcription and its repositioning even in the absence of neuronal excitation. Presented results provide novel insight into the role of BDNF in epileptogenesis. Moreover, they strengthen the statement that this particular gene is a good candidate to search for a new generation of antiepileptic therapies.
Highlights
The Brain-Derived Neurotrophic Factor (BDNF) is one of the most important neurotrophins in the brain
It is known that BDNF is involved in the event of aberrant synaptic plasticity called mossy fiber sprouting, observed in temporal lobe epilepsy (TLE), which is one of the most common types of epilepsy in adults [11]
Experiments performed on animals and in vitro models showed that BDNF causes hypertrophy of granule neurons [16] and increased mossy fiber branching [17]
Summary
The Brain-Derived Neurotrophic Factor (BDNF) is one of the most important neurotrophins in the brain. Acting via its synaptic receptor Tropomyosin-related kinase B (TrkB), BDNF is involved in neuronal differentiation, survival, and synaptic plasticity [1,2,3] It plays an important role in the number of neurological and psychiatric disorders such as Parkinson’s disease [4], schizophrenia [5], depression [6], bipolar disease [7], and epilepsy [8,9,10]. It is known that BDNF is involved in the event of aberrant synaptic plasticity called mossy fiber sprouting, observed in temporal lobe epilepsy (TLE), which is one of the most common types of epilepsy in adults [11]. Those findings support the involvement of BDNF in the aberrant synapse formation in TLE, underlying molecular mechanisms are still not clear
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