Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome
Tóm tắt
Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the MECP2 gene. MECP2-null mice show imbalances in neuronal excitability and synaptic communications. Several previous studies indicate that augmenting synaptic GABA receptors (GABAARs) can alleviate RTT-like symptoms in mice. In addition to the synaptic GABAARs, there is a group of GABAARs found outside the synaptic cleft with the capability to produce sustained inhibition, which may be potential therapeutic targets for the control of neuronal excitability in RTT. Wild-type and MECP2-null mice were randomly divided into four groups, receiving the extrasynaptic GABAAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP) and vehicle control, respectively. Low-dose THIP was administered to neonatal mice through lactation. RTT-like symptoms including lifespan, breathing, motor function, and social behaviors were studied when mice became mature. Changes in neuronal excitability and norepinephrine biosynthesis enzyme expression were studied in electrophysiology and molecular biology. With no evident sedation and other adverse side effects, early-life exposure to THIP extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors of MECP2-null mice. Such beneficial effects were associated with stabilization of locus coeruleus neuronal excitability and improvement of norepinephrine biosynthesis enzyme expression. THIP treatment in early lives might be a therapeutic approach to RTT-like symptoms in MECP2-null mice and perhaps in people with RTT as well.
Tài liệu tham khảo
Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56:422–37.
Johnson CM, Cui N, Zhong W, Oginsky MF, Jiang C. Breathing abnormalities in a female mouse model of Rett syndrome. J Physiol Sci. 2015;65:451–9.
Lioy DT, Wu WW, Bissonnette JM. Autonomic dysfunction with mutations in the gene that encodes methyl-CpG-binding protein 2: insights into Rett syndrome. Auton Neurosci. 2011;161:55–62.
Taneja P, Ogier M, Brooks-Harris G, Schmid DA, Katz DM, Nelson SB. Pathophysiology of locus ceruleus neurons in a mouse model of Rett syndrome. J Neurosci. 2009;29:12187–95.
Ramirez JM, Ward CS, Neul JL. Breathing challenges in Rett syndrome: lessons learned from humans and animal models. Respir Physiol Neurobiol. 2013;189:280–7.
Zhang X, Su J, Cui N, Gai H, Wu Z, Jiang C. The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome. Am J Physiol Cell Physiol. 2011;301:C729–38.
Zhang X, Cui N, Wu Z, Su J, Tadepalli JS, Sekizar S, Jiang C. Intrinsic membrane properties of locus coeruleus neurons in MECP2-null mice. Am J Physiol Cell Physiol. 2010;298:C635–46.
Jin X, Zhong W, Jiang C. Time-dependent modulation of GABA(A)-ergic synaptic transmission by allopregnanolone in locus coeruleus neurons of MECP2-null mice. Am J Physiol Cell Physiol. 2013;305:C1151–60.
Jin X, Cui N, Zhong W, Jin XT, Jiang C. GABAergic synaptic inputs of locus coeruleus neurons in wild-type and MECP2-null mice. Am J Physiol Cell Physiol. 2013;304:C844–57.
Oginsky MF, Cui N, Zhong W, Johnson CM, Jiang C. Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome. Am J Physiol Cell Physiol. 2014;307:C508–20.
Medrihan L, Tantalaki E, Aramuni G, Sargsyan V, Dudanova I, Missler M, Zhang W. Early defects of GABAergic synapses in the brain stem of a MECP2 mouse model of Rett syndrome. J Neurophysiol. 2008;99:112–21.
Zhong W, Cui N, Jin X, Oginsky MF, Wu Y, Zhang S, Bondy B, Johnson CM, Jiang C. Methyl CpG binding protein 2 gene disruption augments tonic currents of gamma-aminobutyric acid receptors in locus coeruleus neurons: impact on neuronal excitability and breathing. J Biol Chem. 2015;290:18400–11.
Roth T, Lines C, Vandormael K, Ceesay P, Anderson D, Snavely D. Effect of gaboxadol on patient-reported measures of sleep and waking function in patients with Primary Insomnia: results from two randomized, controlled, 3-month studies. J Clin Sleep Med. 2010;6:30–9.
Kjaer M, Nielsen H. The analgesic effect of the GABA-agonist THIP in patients with chronic pain of malignant origin. A phase-1-2 study. Br J Clin Pharmacol. 1983;16:477–85.
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: relevance to postpartum depression. Neuron. 2008;59:207–13.
Wu Y, Zhong W, Cui N, Johnson CM, Xing H, Zhang S, Jiang C. Characterization of Rett syndrome-like phenotypes in MECP2-knockout rats. J Neurodev Disord. 2016;8:23.
Samaco RC, Mandel-Brehm C, McGraw CM, Shaw CA, McGill BE, Zoghbi HY. Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome. Nat Genet. 2012;44:206–11.
Kerr B, Alvarez-Saavedra M, Saez MA, Saona A, Young JI. Defective body-weight regulation, motor control and abnormal social interactions in MECP2 hypomorphic mice. Hum Mol Genet. 2008;17:1707–17.
Viemari JC, Roux JC, Tryba AK, Saywell V, Burnet H, Pena F, Zanella S, Bevengut M, Barthelemy-Requin M, Herzing LB, et al. MECP2 deficiency disrupts norepinephrine and respiratory systems in mice. J Neurosci. 2005;25:11521–30.
Wesson DR, Camber S, Harkey M, Smith DE. Diazepam and desmethyldiazepam in breast milk. J Psychoactive Drugs. 1985;17:55–6.
Dusci LJ, Good SM, Hall RW, Ilett KF. Excretion of diazepam and its metabolites in human milk during withdrawal from combination high dose diazepam and oxazepam. Br J Clin Pharmacol. 1990;29:123–6.
Borgatta L, Jenny RW, Gruss L, Ong C, Barad D. Clinical significance of methohexital, meperidine, and diazepam in breast milk. J Clin Pharmacol. 1997;37:186–92.
Gaboxadol hydrobromide [http://chem.sis.nlm.nih.gov/chemidplus/rn/65202-63-3]. Accessed 8 Oct 2016.
Egawa K, Kitagawa K, Inoue K, Takayama M, Takayama C, Saitoh S, Kishino T, Kitagawa M, Fukuda A. Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome. Sci Transl Med. 2012;4:163ra157.
Olmos-Serrano JL, Corbin JG, Burns MP. The GABA(A) receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome. Dev Neurosci. 2011;33:395–403.
Olmos-Serrano JL, Paluszkiewicz SM, Martin BS, Kaufmann WE, Corbin JG, Huntsman MM. Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J Neurosci. 2010;30:9929–38.
Boyle J, Danjou P, Alexander R, Calder N, Gargano C, Agrawal N, Fu I, McCrea JB, Murphy MG. Tolerability, pharmacokinetics and night-time effects on postural sway and critical flicker fusion of gaboxadol and zolpidem in elderly subjects. Br J Clin Pharmacol. 2009;67:180–90.
Kesisoglou F, Balakrishnan A, Manser K. Utility of PBPK absorption modeling to guide modified release formulation development of gaboxadol, a highly soluble compound with region-dependent absorption. J Pharm Sci. 2016;105:722-28.
Cremers T, Ebert B. Plasma and CNS concentrations of Gaboxadol in rats following subcutaneous administration. Eur J Pharmacol. 2007;562:47–52.
Schultz B, Aaes-Jorgensen T, Bogeso KP, Jorgensen A. Preliminary studies on the absorption, distribution, metabolism, and excretion of THIP in animal and man using 14C-labelled compound. Acta Pharmacol Toxicol (Copenh). 1981;49:116–24.
Katz DM, Dutschmann M, Ramirez JM, Hilaire G. Breathing disorders in Rett syndrome: progressive neurochemical dysfunction in the respiratory network after birth. Respir Physiol Neurobiol. 2009;168:101–8.
Zoghbi HY, Percy AK, Glaze DG, Butler IJ, Riccardi VM. Reduction of biogenic amine levels in the Rett syndrome. N Engl J Med. 1985;313:921–4.
Roux JC, Dura E, Moncla A, Mancini J, Villard L. Treatment with desipramine improves breathing and survival in a mouse model for Rett syndrome. Eur J Neurosci. 2007;25:1915–22.
Chandler DJ. Evidence for a specialized role of the locus coeruleus noradrenergic system in cortical circuitries and behavioral operations. Brain Res. 1641;2016:197–206.
Zhang X, Su J, Rojas A, Jiang C. Pontine norepinephrine defects in MECP2-null mice involve deficient expression of dopamine beta-hydroxylase but not a loss of catecholaminergic neurons. Biochem Biophys Res Commun. 2010;394:285–90.
Roux JC, Panayotis N, Dura E, Villard L. Progressive noradrenergic deficits in the locus coeruleus of MECP2 deficient mice. J Neurosci Res. 2010;88:1500–9.
Kow LM, Pfaff DW. Responses of ventromedial hypothalamic neurons in vitro to norepinephrine: dependence on dose and receptor type. Brain Res. 1987;413:220–8.
Brickley SG, Mody I. Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease. Neuron. 2012;73:23–34.
Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. 2005;6:215–29.
Whissell PD, Lecker I, Wang DS, Yu J, Orser BA. Altered expression of deltaGABAA receptors in health and disease. Neuropharmacology. 2015;88:24–35.
Lee CY, Liou HH. GABAergic tonic inhibition is regulated by developmental age and epilepsy in the dentate gyrus. Neuroreport. 2013;24:515–9.
Chen L, Chen K, Lavery LA, Baker SA, Shaw CA, Li W, Zoghbi HY. MECP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome. Proc Natl Acad Sci U S A. 2015;112:5509–14.
Sigel E, Steinmann ME. Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012;287:40224–31.
Mortensen M, Ebert B, Wafford K, Smart TG. Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors. J Physiol. 2010;588:1251–68.
Korsgaard S, Casey DE, Gerlach J, Hetmar O, Kaldan B, Mikkelsen LB. The effect of tetrahydroisoxazolopyridinol (THIP) in tardive dyskinesia: a new gamma-aminobutyric acid agonist. Arch Gen Psychiatry. 1982;39:1017–21.
Braat S, Kooy RF. Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials. Neuropharmacology. 2015;88:48–54.
Zhang W, Peterson M, Beyer B, Frankel WN, Zhang ZW. Loss of MECP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures. J Neurosci. 2014;34:2754–63.
Schwarz LA, Miyamichi K, Gao XJ, Beier KT, Weissbourd B, DeLoach KE, Ren J, Ibanes S, Malenka RC, Kremer EJ, Luo L. Viral-genetic tracing of the input-output organization of a central noradrenaline circuit. Nature. 2015;524:88–92.
Lee V, Maguire J. The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front Neural Circuits. 2014;8:3.
Weng SJ, Wiggins JL, Peltier SJ, Carrasco M, Risi S, Lord C, Monk CS. Alterations of resting state functional connectivity in the default network in adolescents with autism spectrum disorders. Brain Res. 2010;1313:202–14.
Smrt RD, Pfeiffer RL, Zhao X. Age-dependent expression of MECP2 in a heterozygous mosaic mouse model. Hum Mol Genet. 2011;20:1834–43.
Young JI, Zoghbi HY. X-chromosome inactivation patterns are unbalanced and affect the phenotypic outcome in a mouse model of rett syndrome. Am J Hum Genet. 2004;74:511–20.
Wither RG, Lang M, Zhang L, Eubanks JH. Regional MECP2 expression levels in the female MECP2-deficient mouse brain correlate with specific behavioral impairments. Exp Neurol. 2013;239:49–59.
Meziane H, Ouagazzal AM, Aubert L, Wietrzych M, Krezel W. Estrous cycle effects on behavior of C57BL/6 J and BALB/cByJ female mice: implications for phenotyping strategies. Genes Brain Behav. 2007;6:192–200.
Ure K, Lu H, Wang W, Ito-Ishida A, Wu Z, He LJ, Sztainberg Y, Chen W, Tang J, Zoghbi HY. Restoration of MECP2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. Elife. 2016;5:e14198.
Bangasser DA, Zhang X, Garachh V, Hanhauser E, Valentino RJ. Sexual dimorphism in locus coeruleus dendritic morphology: a structural basis for sex differences in emotional arousal. Physiol Behav. 2011;103:342–51.
Jin X, Li S, Bondy B, Zhong W, Oginsky MF, Wu Y, Johnson CM, Zhang S, Cui N, Jiang C. Identification of a group of GABAergic neurons in the dorsomedial area of the locus coeruleus. PLoS One. 2016;11:e0146470.