Dataset Information

Hyperactivation of BDNF-TrkB signaling cascades in human hypothalamic hamartoma (HH): a potential mechanism contributing to epileptogenesis.

ABSTRACT:

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 PLC?1 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 PLC?1 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.

SUBMITTER: Semaan S

PROVIDER: S-EPMC6495156 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Publications

Hyperactivation of BDNF-TrkB signaling cascades in human hypothalamic hamartoma (HH): a potential mechanism contributing to epileptogenesis.

Semaan Suzan S Wu Jie J Gan Yan Y Jin Yu Y Li Guo-Hui GH Kerrigan John F JF Chang Yong-Chang YC Huang Yao Y

CNS neuroscience & therapeutics 20141013 2

<h4>Aims</h4>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.<h4>Met ...[more]

PMID: 25307426

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Project description:OBJECTIVE:Little is known about the intrinsic electrophysiological properties of hypothalamic hamartoma (HH) in vivo and seizure network since only few cases using stereoelectroencephalography (SEEG) electrodes exploring both cortex and HH have been published. To elucidate these issues, we analyzed simultaneous SEEG recordings in HH and cortex systematically. METHODS:We retrospectively investigated data from 15 consecutive patients with SEEG electrodes into the HH for the treatment purpose of radiofrequency thermocoagulation treatment. Additional SEEG electrodes were placed into the cortex in 11 patients to assess extra-HH involvement. Interictal discharges within the HH and anatomo-electroclinical correlations during seizures of each patient were qualitatively and quantitatively analyzed. RESULTS:Overall, 77 electrodes with 719 contacts were implanted, and 33 spontaneous seizures were recorded during long-term SEEG monitoring. Interictally, distinct electrophysiological patterns, including isolated intermittent spikes/sharp waves, burst spike and wave trains, paroxysmal fast discharges, periodic discharges, and high-frequency oscillations, were identified within the HH. Notably, synchronized or independent interictal discharges in the cortex were observed. Regarding the ictal discharges, the electrical onset pattern within the HH always started with abrupt giant shifts superimposed on low-voltage fast activity across patients. The gelastic seizure network mainly involved the HH, orbitofrontal areas, and cingulate gyrus. Seizures with automatisms and impaired awareness primarily propagated to mesial temporal lobes. Moreover, independent ictal discharges arising from the mesial temporal lobe were detected in three out of nine patients. INTERPRETATION:This study comprehensively reveals intrinsic electrophysiological patterns and epileptogenic networks in vivo, providing new insights into the mechanisms underlying cortical and subcortical epileptogenesis.

Dataset Information

Hyperactivation of BDNF-TrkB signaling cascades in human hypothalamic hamartoma (HH): a potential mechanism contributing to epileptogenesis.

Aims

Methods

Results

Conclusion

Publications

Hyperactivation of BDNF-TrkB signaling cascades in human hypothalamic hamartoma (HH): a potential mechanism contributing to epileptogenesis.

Similar Datasets

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