Seizure-induced 5-HT release and chronic impairment of serotonergic function in rats

Lin, Wanhui; Huang, Huapin; Lin, Ming-Xing; Chen, Shenggen; Lv, Xi; Che, Chun‐Hui; Lin, Ji-lan

doi:10.1016/j.neulet.2012.12.007

Cited by 28 publications

(29 citation statements)

References 20 publications

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“…In the same way, FRs reflect bursts of population spikes due to the synchronous firing of granule cells in the dentate gyrus and of pyramidal cells in the hippocampus (Bragin et al, 2007a(Bragin et al, , 2007b(Bragin et al, , 2011, and serotonergic fibers project from the raphe nucleus to the granule and pyramidal cells via interneurons that could influence electrical activity of b r a i n r e s e a r c h 1 5 8 3 ( 2 0 1 4 ) 2 1 1 -2 1 9 principal cells (Andrade and Nicoll, 1987;Klancnik et al, 1991), additional support to our hypothesis comes from a decrease found in serotonin level reported in the rat hippocampus 14 days after the induction of SE with pilocarpine, followed by a decrease in the number of tryptophan hydroxylase serotonergic-neurons in the raphe nucleus 28 days after SE induction (Lin et al, 2013). We speculate that this loss of serotonergic function may favor the generation of FRs soon after the development of SE, supporting the modulatory influence of serotonin on FR activity.…”

Section: Discussionsupporting

confidence: 62%

Serotonin modulates fast ripple activity in rats with spontaneous recurrent seizures

2014

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Section: Discussionsupporting

confidence: 62%

Serotonin modulates fast ripple activity in rats with spontaneous recurrent seizures

2014

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“…The absence of significant differences of monoamine MHPG, 5-HIAA and HVA levels between the three groups was unexpected as these neurotransmitter systems are most commonly implicated in seizure modulation [4,7]. Hippocampal 5-HT is increased acutely in a rodent pilocarpine model of status epilepticus, with subsequent rise of 5-HIAA levels both in hippocampus and CSF [6]. Subsequently, both levels decreased below baseline levels despite the evolution of spontaneous seizure activity, which was ascribed to decreased production of 5-HT in the brainstem.…”

Section: Discussionmentioning

confidence: 99%

“…The precision of this methodology is high and was validated with specific gas chromatographic-mass spectrometric (GS-MS) assays for each metabolite [20]. Overall, monoamine metabolite levels are relatively stable and more reliable than monoamine levels in the CSF [5] because monoamines are rapidly metabolized in brain tissue [6]. …”

Section: Methodsmentioning

confidence: 99%

“…Their metabolites are increased both in epileptogenic tissue as well as in the cerebrospinal fluid in people with chronic epilepsy undergoing resective surgery [5]. In rodent hippocampi, 5-HT release was briefly increased immediately after onset of pilocarpine-induced status epilepticus, whereas its main metabolite, 5-hydroxyindolacetic acid (5-HIAA) increased only two days later, indicating that the 5-HT was being metabolized locally [6]. While the 5-HIAA increases in the CSF lasted weeks, both 5-HT and 5-HIAA levels eventually decreased to below baseline levels, reflecting possible injury to the raphe nuclei.…”

Section: Introductionmentioning

confidence: 99%

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Cerebrospinal Fluid Levels of Monoamine Metabolites in the Epileptic Baboon

2015

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The baboon represents a natural model for genetic generalized epilepsy and sudden unexpected death in epilepsy (SUDEP). In this retrospective study, cerebrospinal fluid (CSF) monoamine metabolites and scalp electroencephalography (EEG) were evaluated in 263 baboons of a pedigreed colony. CSF monoamine abnormalities have been linked to reduced seizure thresholds, behavioral abnormalities and SUDEP in various animal models of epilepsy. The levels of 3-hydroxy-4-methoxyphenylglycol, 5-hydroxyindolacetic acid and homovanillic acid in CSF samples drawn from the cisterna magna were analyzed using high-performance liquid chromatography. These levels were compared between baboons with seizures (SZ), craniofacial trauma (CFT) and asymptomatic, control (CTL) baboons, between baboons with abnormal and normal EEG studies. We hypothesized that the CSF levels of major monoaminergic metabolites (i.e., dopamine, serotonin and norepinephrine) associate with the baboons’ electroclinical status and thus can be used as clinical biomarkers applicable to seizures/epilepsy. However, despite apparent differences in metabolite levels between the groups, usually lower in SZ and CFT baboons and in baboons with abnormal EEG studies, we did not find any statistically significant differences using a logistic regression analysis. Significant correlations between the metabolite levels, especially between 5-HIAA and HVA, were preserved in all electroclinical groups. While we were not able to demonstrate significant differences in monoamine metabolites in relation to seizures or EEG markers of epilepsy, we cannot exclude the monoaminergic system as a potential source of pathogenesis in epilepsy and SUDEP. A prospective study evaluating serial CSF monoamine levels in baboons with recently witnessed seizures, and evaluation of abnormal expression and function of monoaminergic receptors and transporters within epilepsy-related brain regions, may impact the electroclinical status.

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“…The above monitoring process was carried out for 15 hours per day over a period of four weeks. Spontaneous recurrent seizures (SRSs) were evaluated based on their corresponding frequency (per week) and stage over the chronic epilepsy period [24].…”

Section: Inducing Chronic Epilepsy In Rats By Using Pilocarpinementioning

confidence: 99%

The Role of 5-HTR6 in Mossy Fiber Sprouting: Activating Fyn and p-ERK1/2 in Pilocarpine-Induced Chronic Epileptic Rats

Lin

Huang

Chen

et al. 2017

Cell Physiol Biochem

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Objective: Our primary objective is to verify whether 5-HTR6 is involved in the development of mossy fiber sprouting (MFS), and to determine how the progression of MFS is affected by 5-HTR6. Methods: A total of 90 male adult Sprague-Dawley rats were allocated into either the control group (n=36) or the epileptic group (n=54). Status epilepticus (SE) of rats was induced by the intraperitoneal (i.p.) injection of LiCl-pilocarpine. We conducted our experiments in two stages. The first stage involves equally dividing 36 epileptic rats into three groups with treatments of none, 5-HTR6 antagonist SB-27104 (SB) and vehicle DMSO. Then behavior and electroencephalogram (EEG) of rats were monitored by video-EEG. The second stage involves dividing 126 epileptic rats into seven groups with treatments of none, 10% DMSO, SB (100 µg/kg), Fyn antagonist PP 2 (50 µg/kg), p-ERK1/2 antagonist PD-98059 (30 µg/kg), SB (100 µg/ kg) + PP 2 (50 µg/kg); SB (100 µg/kg) + PD-98059 (30 µg/kg). We also treated 18 rats in the control group of the first stage with 100 µg/kg 5-HTR6 agonist WAY-181187 (WAY). MFS of rats was detected through the approach of Timm's staining. Finally, expressions of 5-HTR6, Fyn, p-ERK1/2 and GAP-3 were qualified and semi-quantified via western blotting or RT-PCR. Results: Induction of SE could stimulate formation of MFS and increased GAP-43 expressions. Expressions of 5-HTR6, Fyn and p-ERK1/2 were also up-regulated with increasing time after establishment of SE models. The development of MFS was remarkably inhibited by SB, PP 2 and PD. Compared to the single antagonist, such an inhibitory effect was enhanced by SB+PD or SB+PP. Moreover, treatment of healthy rats with WAY would contribute to up-regulated Fyn and p-ERK1/2 expressions, as well as development of MFS (P < 0.05). Suppression of Fyn triggered a down-regulating trend of p-ERK1/2 (P < 0.05), however, suppressed p-ERK1/2 did not have such a significant effect on Fyn expression. Conclusion: HTR6 may affect the progression of MFS by activating both p-ERK1/2 and Fyn, which further modulate the expression of GAP-43.W. Lin and W. Huang contributed equally to this work.

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Seizure-induced 5-HT release and chronic impairment of serotonergic function in rats

Cited by 28 publications

References 20 publications

Serotonin modulates fast ripple activity in rats with spontaneous recurrent seizures

Serotonin modulates fast ripple activity in rats with spontaneous recurrent seizures

Cerebrospinal Fluid Levels of Monoamine Metabolites in the Epileptic Baboon

The Role of 5-HTR6 in Mossy Fiber Sprouting: Activating Fyn and p-ERK1/2 in Pilocarpine-Induced Chronic Epileptic Rats

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