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Characterization of the CA1 pyramidal neurons in rat model of hepatic cirrhosis: insights into their electrophysiological properties

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Abstract

Although the key contributors of altering neurological function in hepatic encephalopathy are relatively well known, the electrophysiological mechanism of CA1 damage, a key vulnerable area during hyperammonemia, have not yet been defined. Therefore, here we focus on the electrophysiological mechanisms of cognitive impairments following bile duct ligation (BDL). We performed patch-clamp recordings from the CA1 pyramidal neurons in hippocampus of male Wistar rats, which underwent sham or BDL surgery. A striking electrophysiological change of hippocampal neurons in experimental model of BDL was observed in the present study. Spontaneous firing frequency and rate of action potential (AP) rebound was decreased and afterhyperpolarization amplitude (AHP) was increased significantly in hippocampal cells of BDL animals compared to sham group. Together, the results suggest that altered intrinsic properties of the hippocampal neurons may contribute to the cognitive abnormalities during hepatic encephalopathy (HE), highlighting the electrophysiological mechanisms for providing new treatments against HE.

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Abbreviations

HC:

Hepatic cirrhosis

BDL:

Bile duct ligation

HE:

Hepatic encephalopathy

AP:

Action potential

AHP:

Afterhyperpolarization amplitude

LTP:

Long-term potentiation

NO:

Nitric oxide

cGMP-PK:

Cyclic GMP-dependent protein kinase

PDE:

Phosphodiesterase

HE:

hepatic encephalopathy

References

  • Aghaei I, Shabani M, Doustar N, Nazeri M, Dehpour A (2014) Peroxisome proliferator-activated receptor-γ activation attenuates motor and cognition impairments induced by bile duct ligation in a rat model of hepatic cirrhosis. Pharmacol Biochem Behav 120:133–139

    Article  CAS  PubMed  Google Scholar 

  • Aghaei I, Nazeri M, Shabani M, Mossavinasab M, Mirhosseini FK, Nayebpour M et al (2015) Erythropoietin ameliorates the motor and cognitive function impairments in a rat model of hepatic cirrhosis. Metab Brain Dis 30(1):197–204

    Article  CAS  PubMed  Google Scholar 

  • Aghaei I, Hajali V, Dehpour A, Haghani M, Sheibani V, Shabani M (2016) Alterations in the intrinsic electrophysiological properties of Purkinje neurons in a rat model of hepatic encephalopathy: relative preventing effect of PPARγ agonist. Brain Res Bull 121:16–25

    Article  CAS  PubMed  Google Scholar 

  • Ahmadi S, Poureidi M, Rostamzadeh J (2015) Hepatic encephalopathy induces site-specific changes in gene expression of GluN1 subunit of NMDA receptor in rat brain. Metab Brain Dis 30(4):1035–1041

    Article  CAS  PubMed  Google Scholar 

  • Allert N, Köller H, Siebler M (1998) Ammonia-induced depolarization of cultured rat cortical astrocytes. Brain Res 782(1):261–270

    Article  CAS  PubMed  Google Scholar 

  • Arias N, Fidalgo C, Vallejo G, Arias JL (2014) Brain network function during shifts in learning strategies in portal hypertension animals. Brain Res Bull 104:52–59

    Article  PubMed  Google Scholar 

  • Blaine JT, Ribera AB (2001) Kv2 channels form delayed-rectifier potassium channels in situ. J Neurosci 21(5):1473–1480

    CAS  PubMed  Google Scholar 

  • Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361(6407):31–39

    Article  CAS  PubMed  Google Scholar 

  • Boulton C, Southam E, Garthwaite J (1995) Nitric oxide-dependent long-term potentiation is blocked by a specific inhibitor of soluble guanylyl cyclase. Neuroscience 69(3):699–703

    Article  CAS  PubMed  Google Scholar 

  • Braissant O (2010) Current concepts in the pathogenesis of urea cycle disorders. Mol Genet Metab 100:S3–S12

    Article  CAS  PubMed  Google Scholar 

  • Bushara KO, Goebel SU, Shill H, Goldfarb LG, Hallett M (2001) Gluten sensitivity in sporadic and hereditary cerebellar ataxia. Ann Neurol 49(4):540–543

    Article  CAS  PubMed  Google Scholar 

  • Butterworth RF, Norenberg MD, Felipo V, Ferenci P, Albrecht J, Blei AT (2009) Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int 29(6):783–788

    Article  PubMed  Google Scholar 

  • Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM (2005) Age-and region-dependent alterations in Aβ-degrading enzymes: implications for Aβ-induced disorders. Neurobiol Aging 26(5):645–654

    Article  CAS  PubMed  Google Scholar 

  • Cauli O, Llansola M, Erceg S, Felipo V (2006) Hypolocomotion in rats with chronic liver failure is due to increased glutamate and activation of metabotropic glutamate receptors in substantia nigra. J Hepatol 45(5):654–661

    Article  CAS  PubMed  Google Scholar 

  • Cauli O, Mansouri MT, Agusti A, Felipo V. Hyperammonemia increases GABAergic tone in the cerebellum but decreases it in the rat cortex. Gastroenterology. 2009;136(4):1359–67. e2.

  • Çelik T, Gören MZ, Çınar K, Gürdal H, Önder FO, Tan A et al (2005) Fatigue of cholestasis and the serotoninergic neurotransmitter system in the rat. Hepatology 41(4):731–737

    Article  PubMed  Google Scholar 

  • Dhanda S, Sandhir R (2015) Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy. Behav Brain Res 286:222–235

    Article  CAS  PubMed  Google Scholar 

  • ElMlili N, Boix J, Ahabrach H, Rodrigo R, Errami M, Felipo V (2010) Chronic hyperammonemia induces tonic activation of NMDA receptors in cerebellum. J Neurochem 112(4):1005–1014

    Article  CAS  PubMed  Google Scholar 

  • El-Mlili N, Rodrigo R, Naghizadeh B, Cauli O, Felipo V (2008) Chronic hyperammonemia reduces the activity of neuronal nitric oxide synthase in cerebellum by altering its localization and increasing its phosphorylation by calcium-calmodulin kinase II. J Neurochem 106(3):1440–1449

    Article  CAS  PubMed  Google Scholar 

  • Fahmy SR (2015) Anti-fibrotic effect of Holothuria arenicola extract against bile duct ligation in rats. BMC Complement Altern Med 15(1):1

    Article  Google Scholar 

  • Felipo V (2013) Hepatic encephalopathy: effects of liver failure on brain function. Nat Rev Neurosci 14(12):851–858

    Article  CAS  PubMed  Google Scholar 

  • Hermenegildo C, Montoliu C, Llansola M, Muñoz MD, Gaztelu JM, Miñana MD et al (1998) Chronic hyperammonemia impairs the glutamate–nitric oxide–cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur J Neurosci 10(10):3201–3209

    Article  CAS  PubMed  Google Scholar 

  • Huang L-T, Tiao M-M, Tain Y-L, Chen C-C, Hsieh C-S (2009) Melatonin ameliorates bile duct ligation-induced systemic oxidative stress and spatial memory deficits in developing rats. Pediatr Res 65(2):176–180

    Article  CAS  PubMed  Google Scholar 

  • Johnston J, Forsythe ID, Kopp-Scheinpflug C (2010) SYMPOSIUM REVIEW: Goineg native: voltage-gated potassium channels controlling neuronal excitability. J Physiol 588(17):3187–3200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jover R, Rodrigo R, Felipo V, Insausti R, Sáez-Valero J, García-Ayllón M et al (2006) Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: a model of hepatic encephalopathy in cirrhosis. Hepatology 43(6):1257–1266

    Article  CAS  PubMed  Google Scholar 

  • Leke R, Oliveira DL, Forgiarini LF, Escobar TD, Hammes TO, Meyer FS et al (2013) Impairment of short term memory in rats with hepatic encephalopathy due to bile duct ligation. Metab Brain Dis 28(2):187–192

    Article  PubMed  Google Scholar 

  • Li T, Wang N, Zhao M (2012) Neuroprotective effect of phosphocreatine on focal cerebral ischemia-reperfusion injury. Biomed Res Int 2012:168756

    Google Scholar 

  • Llansola M, Montoliu C, Cauli O, Hernández-Rabaza V, Agustí A, Cabrera-Pastor A et al (2013) Chronic hyperammonemia, glutamatergic neurotransmission and neurological alterations. Metab Brain Dis 28(2):151–154

    Article  CAS  PubMed  Google Scholar 

  • Magen I, Avraham Y, Ackerman Z, Vorobiev L, Mechoulam R, Berry EM (2009) Cannabidiol ameliorates cognitive and motor impairments in mice with bile duct ligation. J Hepatol 51(3):528–534

    Article  CAS  PubMed  Google Scholar 

  • Michalak A, Knecht K, Butterworth RF (1997) Hepatic encephalopathy in acute liver failure: role of the glutamate system. Advances in cirrhosis, hyperammonemia, and hepatic encephalopathy. Springer, p. 35–43

  • Monfort P (2002) Muñoz Ma-D, Kosenko E, Felipo V. Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. J Neurosci 22(23):10116–10122

    CAS  PubMed  Google Scholar 

  • Monfort P (2004) Muñoz Ma-D, Felipo V. Hyperammonemia impairs long-term potentiation in hippocampus by altering the modulation of cGMP-degrading phosphodiesterase by protein kinase G. Neurobiol Dis 15(1):1–10

    Article  CAS  PubMed  Google Scholar 

  • Monfort P, Muñoz MD, Felipo V (2005) Chronic hyperammonemia in vivo impairs long-term potentiation in hippocampus by altering activation of cyclic GMP-dependent-protein kinase and of phosphodiesterase 5. J Neurochem 94(4):934–942

    Article  CAS  PubMed  Google Scholar 

  • Monfort P, Erceg S, Piedrafita B, Llansola M, Felipo V (2007) Chronic liver failure in rats impairs glutamatergic synaptic transmission and long-term potentiation in hippocampus and learning ability. Eur J Neurosci 25(7):2103–2111

    Article  PubMed  Google Scholar 

  • Muñoz M-D, Monfort P, Gaztelu J-M, Felipo V (2000) Hyperammonemia impairs NMDA receptor-dependent long-term potentiation in the CA1 of rat hippocampus in vitro. Neurochem Res 25(4):437–441

    Article  PubMed  Google Scholar 

  • Nasehi M, Tackallou SH, Hasani I, Nasehi M (2013a) Cholestasis impaired spatial and non-spatial novelty detection in mice. J Paramedical Sci 4(1):92–98

    Google Scholar 

  • Nasehi M, Yavari SA, Zarrindast MR (2013b) Synergistic effects between CA1 mu opioid and dopamine D1-like receptors in impaired passive avoidance performance induced by hepatic encephalopathy in mice. Psychopharmacology 227(3):553–566

    Article  CAS  PubMed  Google Scholar 

  • Raabe W (1990) Effects of NH4+ on reflexes in cat spinal cord. J Neurophysiol 64(2):565–574

    CAS  PubMed  Google Scholar 

  • Razavinasab M, Moazzami K, Shabani M (2016) Maternal mobile phone exposure alters intrinsic electrophysiological properties of CA1 pyramidal neurons in rat offspring. Toxicol Ind Health 32(6):968–979

    Article  CAS  PubMed  Google Scholar 

  • Rodrigo R, Cauli O (2010) Gomez–Pinedo U, Agusti a, Hernandez–Rabaza V, Garcia–Verdugo JM, et al. hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 139(2):675–684

    Article  CAS  PubMed  Google Scholar 

  • Rodrigo R, Erceg S, Felipo V (2005) Neurons exposed to ammonia reproduce the differential alteration in nitric oxide modulation of guanylate cyclase in the cerebellum and cortex of patients with liver cirrhosis. Neurobiol Dis 19(1):150–161

    Article  CAS  PubMed  Google Scholar 

  • Rudy B, Chow A, Lau D, Amarillo Y, Ozaita A, Saganich M et al (1999) Contributions of Kv3 channels to neuronal excitability. Ann N Y Acad Sci 868(1):304–343

    Article  CAS  PubMed  Google Scholar 

  • Schmahmann JD (2004) Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci 16(3):367–378

    Article  PubMed  Google Scholar 

  • Schuppan D, Afdhal NH (2008) Liver cirrhosis. Lancet 371(9615):838–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shao LR, Halvorsrud R, Borg-Graham L, Storm JF (1999) The role of BK-type Ca2 + −dependent K+ channels in spike broadening during repetitive firing in rat hippocampal pyramidal cells. J Physiol 521(1):135–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Storm JF (1990) Potassium currents in hippocampal pyramidal cells. Prog Brain Res 83:161–187

    Article  CAS  PubMed  Google Scholar 

  • Szerb JC, Butterworth RF (1992) Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog Neurobiol 39(2):135–153

    Article  CAS  PubMed  Google Scholar 

  • Tripodi V, Contin M, Fernández MA, Lemberg A (2012) Bile acids content in brain of common duct ligated rats. Ann Hepatol 11:930–934

    CAS  PubMed  Google Scholar 

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Acknowledgements

The present manuscript is the result of a research project that was approved by Kerman Medical University and Jiroft University of Medical Science.

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Authors and Affiliations

  1. Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, 76198-13159, Iran

    Mahshid Tahamtan, Vahid Sheibani & Mohammad Shabani

  2. Social Determinants of Health Research Center, Guilan University of Medical Sciences, Rasht, Iran

    Iraj Aghaei

  3. Biochemical Department, Jiroft University of Medical Sciences, Kerman, Iran

    Vahid Pooladvand

  4. Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

    Mohammad Khaksari

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  1. Mahshid Tahamtan
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  2. Iraj Aghaei
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Correspondence to Mohammad Shabani.

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1. Author: Mahshid Tahamtan, Contribution: This author helped to conduct the study and write the manuscript.

2. Author: Iraj Aghaei, Contribution: This author helped to conduct the study and write the manuscript

3. Author: Vahid Pooladvand, Contribution: This author helped for design of study and writing of the manuscript

4. Author: Vahid Sheibani, Contribution: This author helped for writing of the manuscript and data analysis

5. Author: Mohammad Khaksari, Contribution: This author helped for writing of the manuscript.

6. Author: Mohammad Shabani, PhD., Mohammad Shabani was responsible for study design, data analysis, and manuscript preparation.

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The authors declare no conflict of interest.

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Mahshid Tahamtan and Iraj Aghaei contributed equally.

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Tahamtan, M., Aghaei, I., Pooladvand, V. et al. Characterization of the CA1 pyramidal neurons in rat model of hepatic cirrhosis: insights into their electrophysiological properties. Metab Brain Dis 32, 881–889 (2017). https://doi.org/10.1007/s11011-017-9966-7

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  • DOI: https://doi.org/10.1007/s11011-017-9966-7

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