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.

Project description:Objective:To evaluate the feasibility of repeat stereotactic radiofrequency thermocoagulation (re-SRT) for patients with hypothalamic hamartoma (HH) and to clarify clinical and surgical factors for seizure outcomes. Methods:Hypothalamic hamartoma patients with gelastic seizures (GSs) who underwent SRT were retrospectively reviewed. Seizure outcomes were evaluated separately for GS and other types of seizures (non-GS). Surgical complications were compared between re-SRT and first SRT. Clinical and surgical factors related to both seizure recurrences after first SRT and final seizure outcomes were analyzed. Results:Participants comprised 150 patients (92 males; median age at surgery, 8 years; range, 1.7-50 years). Of those, 122 (81.3%) had non-GS. Forty-three patients (28.7%) underwent re-SRT. Freedom from GS was achieved by first SRT in 103 patients (68.7%), second SRT in 30/40 (67.5%), third SRT in 3/10 (30.0%), and fourth SRT in 2/3 (66.7%). Finally, 135 patients (90.0%) became GS-free. Ninety patients (73.8%) achieved non-GS freedom, with first SRT in all except one case. Transient complications were more frequent with first SRT (118/150, 78.7%) than re-SRT (35/56, 62.5%), whereas persistent complications were more frequent with re-SRT (7/56, 12.5%) than with first SRT (3/150, 2.0%). Multivariate analyses revealed only younger age at surgery (?1 year) as related to GS recurrence after first SRT, with no variables affecting final GS outcomes. Meanwhile, seizure type (tonic seizure), intellectual disability, and genetic syndromes were significant factors for both non-GS recurrence and final outcomes. Multiple previous treatments were significantly related to final non-GS outcomes as well. Size and subtype of HH and surgical factors were unrelated to seizure outcomes. Significance:Repeat stereotactic radiofrequency thermocoagulation provides potential opportunities to achieve freedom from recurrent GS, albeit with increased risks of persistent complications. Non-GS and intellectual disability could offer early surgical indications, and repeated ineffective treatments should be avoided.

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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