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Effects of human growth hormone on gonadotropin-releasing hormone neurons in mice
Bhattarai, Janardhan P.,Kim, Shin-Hye,Han, Seong-Kyu,Park, Mi-Jung The Korean Pediatric Society 2010 Clinical and Experimental Pediatrics (CEP) Vol.53 No.9
Purpose: Recombinant human growth hormone (rhGH) has been widely used to treat short stature. However, there are some concerns that growth hormone treatment may induce skeletal maturation and early onset of puberty. In this study, we investigated whether rhGH can directly affect the neuronal activities of of gonadotropin-releasing hormone (GnRH). Methods: We performed brain slice gramicidin-perforated current clamp recording to examine the direct membrane effects of rhGH on GnRH neurons, and a whole-cell voltage-clamp recording to examine the effects of rhGH on spontaneous postsynaptic events and holding currents in immature (postnatal days 13-21) and adult (postnatal days 42-73) mice. Results: In immature mice, all 5 GnRH neurons recorded in gramicidin-perforated current clamp mode showed no membrane potential changes on application of rhGH (0.4, $1{\mu}g/mL$). In adult GnRH neurons, 7 (78%) of 9 neurons tested showed no response to rhGH ($0.2-1{\mu}g/mL$) and 2 neurons showed slight depolarization. In 9 (90%) of 10 immature neurons tested, rhGH did not induce any membrane holding current changes or spontaneous postsynaptic currents (sPSCs). There was no change in sPSCs and holding current in 4 of 5 adult GnRH neurons. Conclusion: These findings demonstrate that rhGH does not directly affect the GnRH neuronal activities in our experimental model.
Bhattarai, Janardhan P,Roa, Juan,Herbison, Allan E,Han, Seong Kyu The Endocrine Society 2014 Endocrinology Vol.155 No.2
<P>The effect of serotonin (5-HT) on the electrical excitability of GnRH neurons was examined using gramicidin perforated-patch electrophysiology in transgenic GnRH-green fluorescent protein mice. In diestrous female, the predominant effect of 5-HT was inhibition (70%) with 50% of these cells also exhibiting a late-onset excitation. Responses were dose dependent (EC(50) = 1.2μM) and persisted in the presence of amino acid receptor antagonists and tetrodotoxin, indicating a predominant postsynaptic action of 5-HT. Studies in neonatal, juvenile, peripubertal, and adult mice revealed that 5-HT exerted less potent responses from GnRH neurons with advancing postnatal age in both sexes. In adult male mice, 5-HT exerted less potent hyperpolarizing responses with more excitations compared with females. In addition, adult proestrous female GnRH neurons exhibited reduced inhibition and a complete absence of biphasic hyperpolarization-excitation responses. Studies using 5-HT receptor antagonists demonstrated that the activation of 5-HT(1A) receptors mediated the inhibitory responses, whereas the excitation was mediated by the activation of 5-HT(2A) receptors. The 5-HT-mediated hyperpolarization involved both potassium channels and adenylate cyclase activation, whereas the 5-HT excitation was dependent on protein kinase C. The effects of exogenous 5-HT were replicated using fluoxetine, which enhances endogenous 5-HT levels. These studies demonstrate that 5-HT exerts a biphasic action on most GnRH neurons whereby a fast 5HT(1A)-mediated inhibition occurs alongside a slow 5-HT(2A) excitation. The balance of 5-HT-evoked inhibition vs excitation is developmentally regulated, sexually differentiated, and variable across the estrous cycle and may play a role in regulation of hypothalamic-pituitary-gonadal axis throughout postnatal development.</P>
Yiming Shen,Janardhan P. Bhattarai,Soo Joung Park,Gyu Seung Lee,Pan Dong Ryu,Seong Kyu Han 대한수의학회 2018 Journal of Veterinary Science Vol.19 No.2
It has been reported that Korean red ginseng (KRG), a valuable and important traditional medicine, has varied effects on the central nervoussystem, suggesting its activities are complicated. The paraventricular nucleus (PVN) neurons of the hypothalamus has a critical role in stressresponses and hormone secretions. Although the action mechanisms of KRG on various cells and systems have been reported, the directmembrane effects of KRG on PVN neurons have not been fully described. In this study, the direct membrane effects of KRG on PVN neuronalactivity were investigated by using a perforated patch-clamp in ICR mice. In gramicidin perforated patch-clamp mode, KRG extract (KRGE)induced repeatable depolarization followed by hyperpolarization of PVN neurons. The KRGE-induced responses were concentrationdependentand persisted in the presence of tetrodotoxin, a voltage sensitive Na+ channel blocker. The KRGE-induced responses weresuppressed by 6-cyano-7-nitroquinoxaline-2,3-dione (10 μM), a non–N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, but notby picrotoxin, a type A gamma-aminobutyric acid receptor antagonist. The results indicate that KRG activates non-NMDA glutamate receptorsof PVN neurons in mice, suggesting that KRG may be a candidate for use in regulation of stress responses by controlling autonomic nervoussystem and hormone secretion.
Seon Ah Park,Hua Yin,Janardhan P. Bhattarai,Soo Joung Park,Seong Kyu Han KOREAN ACADAMY OF ORAL BIOLOGY 2009 International Journal of Oral Biology Vol.34 No.4
Somatostatin (SST) is a known neuromodulator of the central nervous system. The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) receives many thinmyelinated Aδ-fiber and unmyelinated C primary afferent fibers and is involved in nociceptive processing. Many studies have demonstrated that SST plays a pivotal role in pain modulation in the spinal cord. However, little is yet known about the direct effects of SST on the SG neurons of the Vc in adult mice. In our present study, we investigated the direct membrane effects of SST and a type 2 SST receptor agonist, seglitide (SEG), on the SG neurons of the Vc using a gramicidin-perforated current clamp in adult mice. The majority (53%, n = 27/51) of the adult SG neurons were hyperpolarized by SST (300 nM) but no differences were found in the hyperpolarization response rate between males and females. When SST was applied successively, the second response was smaller (76 ± 9.5%, n = 19), suggesting that SST receptors are desensitized by repeated application. SST-induced hyperpolarization was also maintained under conditions where presynaptic events were blocked (75 ± 1.0%, n = 5), suggesting that this neuromodulator exerts direct effects upon postsynaptic SG neurons. SEG was further found to induce membrane hyperpolarization of the SG neurons of the Vc. These results collectively demonstrate that SST inhibits the SG neuronal activities of the Vc in adult mice with no gender bias, and that these effects are mediated via a type 2 SST receptor, suggesting that this is a potential target for orofacial pain modulation.
Hua Yin,Seon Ah Park,Soon Jeong Choi,Janardhan P. Bhattarai,Soo Joung Park,Bong Jik Suh,Seong Kyu Han KOREAN ACADAMY OF ORAL BIOLOGY 2008 International Journal of Oral Biology Vol.33 No.4
Bicuculline is one of the most commonly used GABAA receptor antagonists in electrophysiological research. Because of its poor water solubility, bicuculline quaternary ammonium salts such as bicuculline methiodide (BMI) and bicuculline methbromide are preferred. However, a number of studies have shown that BMI has non-GABAA receptormediated effects. The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) is implicated in the processing of nociceptive signaling. In this study, we investigated whether BMI has non-GABA receptormediated activity in Vc SG neurons using a whole cell patch clamp technique. SG neurons were depolarized by application of BMI (20 μM) using a high Cl-pipette solution. GABA (30-100 μM) also induced membrane depolarization of SG neuron. Although BMI is known to be a GABAA receptor antagonist, GABA-induced membrane depolarization was enhanced by co-application with BMI. However, free base bicuculline (fBIC) and picrotoxin (PTX), a GABAA and GABAC receptor antagonist, blocked the GABAinduced response. Furthermore, BMI-induced membrane depolarization persisted in the presence of PTX or an antagonist cocktail consisting of tetrodotoxin (Na+ channel blocker), AP-5 (NMDA receptor antagonist), CNQX (non-NMDA receptor antagonist), and strychnine (glycine receptor antagonist). Thus BMI induces membrane depolarization by directly acting on postsynaptic Vc SG neurons in a manner which is independent of GABAA receptors. These results suggest that other unknown mechanisms may be involved in BMI-induced membrane depolarization.