Hyperactivation of<scp>BDNF</scp>‐TrkB Signaling Cascades in Human Hypothalamic Hamartoma (<scp>HH</scp>): A Potential Mechanism Contributing to Epileptogenesis

Semaan, Suzan M.; Wu, Jie; Gan, Yunhua; Yu, Jin; Li, Guohui; Kerrigan, John F.; Chang, Yongchang; Huang, Yao

doi:10.1111/cns.12331

Cited by 13 publications

(12 citation statements)

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“…Paradoxical excitation in response to GABA is likely due to reversal of the intracellular chloride ion gradient associated with the expression profile of NKCC1 and KCC2 (developmentally regulated cation‐chloride transporters within the neuron membrane) . In turn, downregulation of KCC2 expression in HH tissue may be related to hyperactivation of the brain‐derived neurotrophic factor (BDNF)‐trkB signaling pathway …”

Section: Cellular Phenotypesmentioning

confidence: 99%

Hypothalamic hamartoma: Neuropathology and epileptogenesis

et al. 2017

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Hypothalamic hamartomas (HHs) are congenital malformations of the ventral hypothalamus resulting in treatment-resistant epilepsy and are intrinsically epileptogenic for the gelastic seizures that are the hallmark symptom of this disorder. This paper reviews the neuropathologic features of HHs associated with epilepsy, with an emphasis on characterizing neuron phenotypes and an ultimate goal of understanding the cellular model of ictogenesis occurring locally within this tissue. We also present previously unpublished findings on Golgi staining of HH. The microarchitecture of HH is relatively simple, with nodular clusters of neurons that vary in size and abundance with poorly defined boundaries. Approximately 80-90% of HH neurons have an interneuron-like phenotype with small, round soma and short, unbranched processes that lack spines. These neurons express glutamic acid decarboxylase and likely utilize γ-aminobutyric acid (GABA) as their primary neurotransmitter. They have intrinsic membrane properties that lead to spontaneous pacemaker-like firing activity. The remaining HH neurons are large cells with pleomorphic, often pyramidal, soma and dendrites that are more likely to be branched and have spines. These neurons appear to be excitatory, projection-type neurons, and have the functionally immature behavior of depolarizing and firing in response to GABA ligands. We hypothesize that the irregular neuronal clusters are the functional unit for ictogenesis. Further research to define and characterize these local networks is required to fully understand the cellular mechanisms responsible for gelastic seizures.

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Section: Cellular Phenotypesmentioning

confidence: 99%

Hypothalamic hamartoma: Neuropathology and epileptogenesis

et al. 2017

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“…Moreover, seizure-related disorders in humans have recently been associated with KCC2 mutations (Kahle et al, 2014; Puskarjov et al, 2014; Stödberg et al, 2015). Deficits in KCC2 expression levels and/or activity also occur in animal models of chronic stress (Hewitt et al, 2009; MacKenzie and Maguire, 2015; Tsukahara et al, 2015, 2016), trauma (Jin et al, 2005), ischemia (Jaenisch et al, 2010), schizophrenia (Hyde et al, 2011) and in peritumoral regions in human brain (Pallud et al, 2014; Semaan et al, 2015). It remains to be determined if deficits in KCC2 activity and expression directly contribute to these varying pathologies.…”

Section: Introductionmentioning

confidence: 99%

Compromising KCC2 transporter activity enhances the development of continuous seizure activity

et al. 2016

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Impaired neuronal inhibition has long been associated with the increased probability of seizure occurrence and heightened seizure severity. Fast synaptic inhibition in the brain is primarily mediated by the type A γ-aminobutyric acid receptors (GABAARs), ligand-gated ion channels that can mediate Cl− influx resulting in membrane hyperpolarization and the restriction of neuronal firing. In most adult brain neurons, the K+/Cl− co-transporter-2 (KCC2) establishes hyperpolarizing GABAergic inhibition by maintaining low [Cl−]i. In this study, we sought to understand how decreased KCC2 transport function affects seizure event severity. We impaired KCC2 transport in the 0-Mg2+ ACSF and 4-aminopyridine in vitro models of epileptiform activity in acute mouse brain slices. Experiments with the selective KCC2 inhibitor VU0463271 demonstrated that reduced KCC2 transport increased the duration of SLEs, resulting in non-terminating discharges of clonic-like activity. We also investigated slices obtained from the KCC2-Ser940Ala (S940A) point-mutant mouse, which has a mutation at a known functional phosphorylation site causing behavioral and cellular deficits under hyperexcitable conditions. We recorded from the entorhinal cortex of S940A mouse brain slices in both 0-Mg2+ ACSF and 4-aminopyridine, and demonstrated that loss of the S940 residue increased the susceptibility of continuous clonic-like discharges, an in vitro form of status epilepticus. Our experiments revealed KCC2 transport activity is a critical factor in seizure event duration and mechanisms of termination. Our results highlight the need for therapeutic strategies that potentiate KCC2 transport function in order to decrease seizure event severity and prevent the development of status epilepticus.

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“…Semaan et al. reported that multiple brain‐derived norotrophic factor tropomyosin receptor kinase B (BDNF‐TrkB) signaling pathways were activated in HH …”

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confidence: 99%

Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: A prospective trial in 48 patients and review of the literature

et al. 2017

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SUMMARYEpilepsies associated with hypothalamic hamartomas (HHs) are frequently drug resistant with severe psychiatric and cognitive comorbidities. We performed a prospective trial to evaluate the safety and efficacy of Gamma Knife radiosurgery (GKS). Between October 1999 and October 2007, a total of 57 patients were investigated, included and treated by GKS in Timone University Hospital. Preoperative workup and 3-year postoperative evaluation consisted of seizure diary, neuropsychological, psychiatric, endocrinologic, visual field, and visual acuity examinations. Follow-up of >3 years was available for 48 patients. Topologic type was type I in 11 patients, type II in 15, type III in 17, type IV in one, type V in one, type VI in one, and mixed type in 2. The median marginal dose was 17 Gy (min 14 and max 25 Gy). The median target volume was 398 mm 3 (28-1,600 mm 3 ). Due to partial results, 28 patients (58.3%) required a second treatment. The median follow-up was 71 months (36-153 months). At last follow-up, the rate of Engel class I outcome was 39.6%, Engel class II was 29.2% (I+II 68.8%), and Engel class III was 20%. Global psychiatric comorbidity was considered cured in 28%, improved in 56%, stable in 8%, and continued to worsen in 8%. No permanent neurologic side effect was reported (in particular, no memory deficit). Nondisabling transient poikilothermia was observed in three patients (6.2%). A transient increase of seizure frequency was reported in 8 patients (16.6%) with a median duration of 30 days (9-90 days). Microsurgery was proposed because of insufficient efficacy of GKS in seven patients (14.5%) with a postoperative Engel class I-II in 28.6%. This prospective trial demonstrates very good long-term safety and efficacy of GKS for 2 patients. Beyond seizure reduction, the improvement of psychiatric and cognitive comorbidities along with better school performance and social functioning, being better socially integrated, having friends having a social life, working, participating to group activities turn out to be major benefits of GKS in this group of patients with frequently catastrophic epilepsy.

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Hyperactivation ofBDNF‐TrkB Signaling Cascades in Human Hypothalamic Hamartoma (HH): A Potential Mechanism Contributing to Epileptogenesis

Abstract: 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.

Cited by 13 publications

References 56 publications

Hypothalamic hamartoma: Neuropathology and epileptogenesis

Hypothalamic hamartoma: Neuropathology and epileptogenesis

Compromising KCC2 transporter activity enhances the development of continuous seizure activity

Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: A prospective trial in 48 patients and review of the literature

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