The highly integrated layers of the epigenome are responsible for the cell type specific and exquisitely environmentally responsive deployment of genes and functional gene networks that underlie the molecular pathophysiology of epilepsy and its associated comorbidities, including but not limited to neurotransmitter receptors (e.g., GluR2, GLRA2, and GLRA3), growth factors (e.g., BDNF), extracellular matrix proteins (e.g., RELN), and diverse transcriptional regulators (e.g., CREB, c-fos, and c-jun).
BDNF has emerged as one of the most important signaling molecules for the developing nervous system as well as the impaired nervous system, and multiple diseases, such as Alzheimer's, Parkinson's, Huntington's, epilepsy, Rett's syndrome, and psychiatric depression, are linked by their association with potential dysregulation of BDNF-driven signal transduction programs.
We report that the seizure-induced decrease in GABA(A)R alpha1 subunit expression associated with epilepsy is mediated by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway regulated by brain-derived neurotrophic factor (BDNF).
Pathologic levels of BDNF-dependent synaptic plasticity may contribute to conditions such as epilepsy and chronic pain sensitization, whereas application of the trophic properties of BDNF may lead to novel therapeutic options in neurodegenerative diseases and perhaps even in neuropsychiatric disorders.
Together, these results suggest that dendritic accumulation of BDNF mRNA and protein plays a critical role in the cellular changes leading to epilepsy.
As nerve growth factor and brain derived neurotrophic factor are the best-studied proteins of this class, we begin by discussing the evidence linking these neurotrophins to epilepsy and seizure.
These data suggest that BDNF and its receptor may play a local role within the hippocampus in kindling-associated neural plasticity and in neuronal protection following epileptic, ischemic, and hypoglycemic insults.