Hyperactivation of BDNF-TrkB signaling cascades in human hypothalamic hamartoma (HH): a potential mechanism contributing to epileptogenesis
| Autor: | Yu Jin, Yan Gan, John F. Kerrigan, Suzan M. Semaan, Yao Huang, Guo‐Hui Li, Yong‐Chang Chang, Jie Wu |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Patch-Clamp Techniques Adolescent Hamartoma Carbazoles Hypothalamus Down-Regulation Tropomyosin receptor kinase B Biology In Vitro Techniques Epileptogenesis Indole Alkaloids Membrane Potentials Young Adult Hypothalamic hamartoma Downregulation and upregulation Physiology (medical) Gelastic seizure medicine Humans Receptor trkB Pharmacology (medical) Enzyme Inhibitors Phosphorylation Child Protein kinase B Pharmacology Brain-derived neurotrophic factor Neurons Membrane Glycoproteins Symporters Brain-Derived Neurotrophic Factor Infant Original Articles Protein-Tyrosine Kinases Psychiatry and Mental health nervous system Child Preschool Tyrosine Female Signal transduction medicine.symptom Neuroscience Hypothalamic Diseases Signal Transduction |
| Zdroj: | CNS neurosciencetherapeutics. 21(2) |
| ISSN: | 1755-5949 |
| Popis: | Summary Aims Although compelling evidence suggests that human hypothalamic hamartoma (HH) is intrinsically epileptogenic for gelastic seizures, the molecular mechanisms responsible for epileptogenesis within HH remain to be elucidated. The aim of this study was to test the hypothesis that hyperactivation of BDNF-TrkB signaling pathways in surgically resected HH tissue is a possible mechanism for downregulation of KCC2 expression, which in turn underlies GABA-mediated excitation within HH. Methods Activation of three major BDNF-TrkB signaling pathways including MAPKs, Akt, and PLCγ1 were evaluated in surgically resected HH tissue (n = 14) versus human hypothalamic control tissue (n = 8) using combined methodologies of biochemistry, molecular biology, cell biology, and electrophysiology. Results Our data show that compared with hypothalamic control tissue, in HH tissue, (i) activation of TrkB and expression of mature BDNF are elevated; (ii) MAPKs (including ERK1/2, p38, and JNK), Akt, and PLCγ1 are highly activated; (iii) KCC2 expression is downregulated; and (iv) pharmacological manipulation of TrkB signaling alters HH neuronal firing rate. Conclusion Our findings suggest that multiple BDNF-TrkB signaling pathways are activated in HH. They act independently or collaboratively to downregulate KCC2 expression, which is the key component for GABA-mediated excitation associated with gelastic seizures. |
| Databáze: | OpenAIRE |
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