Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic
Abstract
:1. Introduction
1.1. Overlapping but Distinct Clinical Phenotypes for Rett Syndrome and CDD
1.2. Decreased Brain Volume, Dendritic Arborization, and Spine Density in RTT and CDD
1.3. Seizures
1.4. Glutamatergic Alterations in RTT and CDD
1.5. Impaired Maturation of the GABAergic System
1.6. The Emerging Role of Astrocytes
1.7. Circuit Homeostasis in RTT
1.8. Sleep in RTT and in CDD
1.9. Insights from Pre-Clinical Studies Targeting Glutamatergic Pathways
2. Current Clinical Trials
2.1. Rett Syndrome
2.2. CDKL5 Deficiency Disorder
2.3. Lessons Learned from Clinical Trials
3. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Hagberg, B. Clinical manifestations and stages of Rett syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 2002, 8, 61–65. [Google Scholar] [CrossRef] [PubMed]
- Operto, F.F.; Mazza, R.; Pastorino, G.M.G.; Verrotti, A.; Coppola, G. Epilepsy and genetic in Rett syndrome: A review. Brain Behav. 2019, 9, e01250. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Neul, J.L.; Zoghbi, H.Y. Rett syndrome: A prototypical neurodevelopmental disorder. Neuroscientist 2004, 10, 118–128. [Google Scholar] [CrossRef] [PubMed]
- Neul, J.L.; Fang, P.; Barrish, J.; Lane, J.; Caeg, E.B.; Smith, E.O.; Zoghbi, H.; Percy, A.; Glaze, D.G. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology 2008, 70, 1313–1321. [Google Scholar] [CrossRef]
- Olson, H.E.; Demarest, S.T.; Pestana-Knight, E.M.; Swanson, L.C.; Iqbal, S.; Lal, D.; Leonard, H.; Cross, J.H.; Devinsky, O.; Benke, T.A. Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review. Pediatr. Neurol. 2019, 97, 18–25. [Google Scholar] [CrossRef]
- Demarest, S.T.; Olson, H.E.; Moss, A.; Pestana-Knight, E.; Zhang, X.; Parikh, S.; Swanson, L.C.; Riley, K.D.; Bazin, G.A.; Angione, K.; et al. CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development. Epilepsia 2019. [Google Scholar] [CrossRef]
- Fehr, S.; Downs, J.; Ho, G.; de Klerk, N.; Forbes, D.; Christodoulou, J.; Williams, S.; Leonard, H. Functional abilities in children and adults with the CDKL5 disorder. Am. J. Med. Genet. A 2016, 170, 2860–2869. [Google Scholar] [CrossRef]
- Fehr, S.; Wong, K.; Chin, R.; Williams, S.; de Klerk, N.; Forbes, D.; Krishnaraj, R.; Christodoulou, J.; Downs, J.; Leonard, H. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology 2016, 87, 2206–2213. [Google Scholar] [CrossRef]
- Fehr, S.; Wilson, M.; Downs, J.; Williams, S.; Murgia, A.; Sartori, S.; Vecchi, M.; Ho, G.; Polli, R.; Psoni, S.; et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur. J. Hum. Genet. 2013, 21, 266–273. [Google Scholar] [CrossRef]
- Tarquinio, D.C.; Hou, W.; Berg, A.; Kaufmann, W.E.; Lane, J.B.; Skinner, S.A.; Motil, K.J.; Neul, J.L.; Percy, A.K.; Glaze, D.G. Longitudinal course of epilepsy in Rett syndrome and related disorders. Brain 2017, 140, 306–318. [Google Scholar] [CrossRef]
- Armstrong, D.D. Rett syndrome neuropathology review 2000. Brain Dev. 2001, 23 (Suppl. 1), S72–S76. [Google Scholar] [CrossRef]
- Subramaniam, B.; Naidu, S.; Reiss, A.L. Neuroanatomy in Rett syndrome: Cerebral cortex and posterior fossa. Neurology 1997, 48, 399–407. [Google Scholar] [CrossRef] [PubMed]
- Naidu, S.; Kaufmann, W.E.; Abrams, M.T.; Pearlson, G.D.; Lanham, D.C.; Fredericksen, K.A.; Barker, P.B.; Horska, A.; Golay, X.; Mori, S.; et al. Neuroimaging studies in Rett syndrome. Brain Dev. 2001, 23 (Suppl. 1), S62–S71. [Google Scholar] [CrossRef]
- Carter, J.C.; Lanham, D.C.; Pham, D.; Bibat, G.; Naidu, S.; Kaufmann, W.E. Selective Cerebral Volume Reduction in Rett Syndrome: A Multiple-Approach MR Imaging Study. AJNR Am. J. Neuroradiol 2008, 29, 436–441. [Google Scholar] [CrossRef] [PubMed]
- Shiohama, T.; Levman, J.; Takahashi, E. Surface- and voxel-based brain morphologic study in Rett and Rett-like syndrome with MECP2 mutation. Int. J. Dev. Neurosci. 2019, 73, 83–88. [Google Scholar] [CrossRef] [PubMed]
- Ward, B.C.; Agarwal, S.; Wang, K.; Berger-Sweeney, J.; Kolodny, N.H. Longitudinal brain MRI study in a mouse model of Rett Syndrome and the effects of choline. Neurobiol. Dis. 2008, 31, 110–119. [Google Scholar] [CrossRef] [PubMed]
- Smith, E.S.; Smith, D.R.; Eyring, C.; Braileanu, M.; Smith-Connor, K.S.; Ei Tan, Y.; Fowler, A.Y.; Hoffman, G.E.; Johnston, M.V.; Kannan, S.; et al. Altered trajectories of neurodevelopment and behavior in mouse models of Rett syndrome. Neurobiol. Learn. Mem. 2018. [Google Scholar] [CrossRef]
- Moroto, M.; Nishimura, A.; Morimoto, M.; Isoda, K.; Morita, T.; Yoshida, M.; Morioka, S.; Tozawa, T.; Hasegawa, T.; Chiyonobu, T.; et al. Altered somatosensory barrel cortex refinement in the developing brain of Mecp2-null mice. Brain Res. 2013, 1537, 319–326. [Google Scholar] [CrossRef]
- Liang, J.S.; Shimojima, K.; Takayama, R.; Natsume, J.; Shichiji, M.; Hirasawa, K.; Imai, K.; Okanishi, T.; Mizuno, S.; Okumura, A.; et al. CDKL5 alterations lead to early epileptic encephalopathy in both genders. Epilepsia 2011, 52, 1835–1842. [Google Scholar] [CrossRef]
- Lee, L.J.; Tsytsarev, V.; Erzurumlu, R.S. Structural and functional differences in the barrel cortex of Mecp2 null mice. J. Comp. Neurol. 2017, 525, 3951–3961. [Google Scholar] [CrossRef]
- Banerjee, A.; Miller, M.T.; Li, K.; Sur, M.; Kaufmann, W.E. Towards a better diagnosis and treatment of Rett syndrome: A model synaptic disorder. Brain 2019, 142, 239–248. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Y.C.; Xiong, Z.Q. Molecular and Synaptic Bases of CDKL5 Disorder. Dev. Neurobiol. 2019, 79, 8–19. [Google Scholar] [CrossRef] [PubMed]
- Ren, E.; Roncace, V.; Trazzi, S.; Fuchs, C.; Medici, G.; Gennaccaro, L.; Loi, M.; Galvani, G.; Ye, K.; Rimondini, R.; et al. Functional and Structural Impairments in the Perirhinal Cortex of a Mouse Model of CDKL5 Deficiency Disorder Are Rescued by a TrkB Agonist. Front. Cell. Neurosci. 2019, 13, 169. [Google Scholar] [CrossRef] [PubMed]
- Della Sala, G.; Putignano, E.; Chelini, G.; Melani, R.; Calcagno, E.; Michele Ratto, G.; Amendola, E.; Gross, C.T.; Giustetto, M.; Pizzorusso, T. Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1. Biol. Psychiatry 2016, 80, 302–311. [Google Scholar] [CrossRef] [PubMed]
- Lupori, L.; Sagona, G.; Fuchs, C.; Mazziotti, R.; Stefanov, A.; Putignano, E.; Napoli, D.; Strettoi, E.; Ciani, E.; Pizzorusso, T. Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder. Hum. Mol. Genet. 2019, 28, 2851–2861. [Google Scholar] [CrossRef] [Green Version]
- Zhu, Y.C.; Li, D.; Wang, L.; Lu, B.; Zheng, J.; Zhao, S.L.; Zeng, R.; Xiong, Z.Q. Palmitoylation-dependent CDKL5-PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development. Proc. Natl. Acad. Sci. USA 2013, 110, 9118–9123. [Google Scholar] [CrossRef]
- Cheng, T.L.; Wang, Z.; Liao, Q.; Zhu, Y.; Zhou, W.H.; Xu, W.; Qiu, Z. MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex. Dev. Cell 2014, 28, 547–560. [Google Scholar] [CrossRef]
- Blue, M.E.; Kaufmann, W.E.; Bressler, J.; Eyring, C.; O’Driscoll, C.; Naidu, S.; Johnston, M.V. Temporal and Regional Alterations in NMDA Receptor Expression in Mecp2-Null Mice. Anat. Rec. 2011, 294, 1624–1634. [Google Scholar] [CrossRef] [Green Version]
- Blue, M.E.; Naidu, S.; Johnston, M.V. Development of amino acid receptors in frontal cortex from girls with Rett syndrome. Ann. Neurol. 1999, 45, 541–545. [Google Scholar] [CrossRef]
- Durand, S.; Patrizi, A.; Quast, K.B.; Hachigian, L.; Pavlyuk, R.; Saxena, A.; Carninci, P.; Hensch, T.K.; Fagiolini, M. NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2. Neuron 2012, 76, 1078–1090. [Google Scholar] [CrossRef]
- Johnston, M.V.; Ammanuel, S.; O’Driscoll, C.; Wozniak, A.; Naidu, S.; Kadam, S.D. Twenty-four hour quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice. Front. Syst. Neurosci. 2014, 8, 118. [Google Scholar] [CrossRef] [PubMed]
- Lo, F.S.; Blue, M.E.; Erzurumlu, R.S. Enhancement of postsynaptic GABAA and extrasynaptic NMDA receptor-mediated responses in the barrel cortex of Mecp2-null mice. J. Neurophysiol. 2016, 115, 1298–1306. [Google Scholar] [CrossRef] [PubMed]
- Banerjee, A.; Rikhye, R.V.; Breton-Provencher, V.; Tang, X.; Li, C.; Li, K.; Runyan, C.A.; Fu, Z.; Jaenisch, R.; Sur, M. Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome. Proc. Natl. Acad. Sci. USA 2016, 113, E7287–E7296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tang, X.; Drotar, J.; Li, K.; Clairmont, C.D.; Brumm, A.S.; Sullins, A.J.; Wu, H.; Liu, X.S.; Wang, J.; Gray, N.S.; et al. Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice. Sci. Transl. Med. 2019, 11. [Google Scholar] [CrossRef] [PubMed]
- Tang, X.; Kim, J.; Zhou, L.; Wengert, E.; Zhang, L.; Wu, Z.; Carromeu, C.; Muotri, A.R.; Marchetto, M.C.; Gage, F.H.; et al. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc. Natl. Acad. Sci. USA 2016, 113, 751–756. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Okuda, K.; Kobayashi, S.; Fukaya, M.; Watanabe, A.; Murakami, T.; Hagiwara, M.; Sato, T.; Ueno, H.; Ogonuki, N.; Komano-Inoue, S.; et al. CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility. Neurobiol. Dis. 2017, 106, 158–170. [Google Scholar] [CrossRef]
- Tramarin, M.; Rusconi, L.; Pizzamiglio, L.; Barbiero, I.; Peroni, D.; Scaramuzza, L.; Guilliams, T.; Cavalla, D.; Antonucci, F.; Kilstrup-Nielsen, C. The antidepressant tianeptine reverts synaptic AMPA receptor defects caused by deficiency of CDKL5. Hum. Mol. Genet. 2018, 27, 2052–2063. [Google Scholar] [CrossRef]
- Dong, Q.; Liu, Q.; Li, R.; Wang, A.; Bu, Q.; Wang, K.H.; Chang, Q. Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes. Elife 2018, 7, e33417. [Google Scholar] [CrossRef]
- Yennawar, M.; White, R.S.; Jensen, F.E. AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder. J. Neurosci. 2019, 39, 4814–4828. [Google Scholar] [CrossRef] [Green Version]
- Glaze, D.G.; Percy, A.K.; Skinner, S.; Motil, K.J.; Neul, J.L.; Barrish, J.O.; Lane, J.B.; Geerts, S.P.; Annese, F.; Graham, J.; et al. Epilepsy and the natural history of Rett syndrome. Neurology 2010, 74, 909–912. [Google Scholar] [CrossRef] [Green Version]
- Moser, S.J.; Weber, P.; Lutschg, J. Rett syndrome: Clinical and electrophysiologic aspects. Pediatr. Neurol. 2007, 36, 95–100. [Google Scholar] [CrossRef] [PubMed]
- Pintaudi, M.; Calevo, M.G.; Vignoli, A.; Parodi, E.; Aiello, F.; Baglietto, M.G.; Hayek, Y.; Buoni, S.; Renieri, A.; Russo, S.; et al. Epilepsy in Rett syndrome: Clinical and genetic features. Epilepsy Behav. 2010, 19, 296–300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jian, L.; Nagarajan, L.; de Klerk, N.; Ravine, D.; Christodoulou, J.; Leonard, H. Seizures in Rett syndrome: An overview from a one-year calendar study. Eur. J. Paediatr. Neurol. 2007, 11, 310–317. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nissenkorn, A.; Gak, E.; Vecsler, M.; Reznik, H.; Menascu, S.; Ben Zeev, B. Epilepsy in Rett syndrome—The experience of a National Rett Center. Epilepsia 2010, 51, 1252–1258. [Google Scholar] [CrossRef] [PubMed]
- Melikishvili, G.; Epitashvili, N.; Tabatadze, N.; Chikvinidze, G.; Dulac, O.; Bienvenu, T.; Gataullina, S. New insights in phenomenology and treatment of epilepsy in CDKL5 encephalopathy. Epilepsy Behav. 2019, 94, 308–311. [Google Scholar] [CrossRef]
- Olson, L.E.; Roper, R.J.; Baxter, L.L.; Carlson, E.J.; Epstein, C.J.; Reeves, R.H. Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes. Dev. Dyn 2004, 230, 581–589. [Google Scholar] [CrossRef]
- Cope, D.W.; Di Giovanni, G.; Fyson, S.J.; Orban, G.; Errington, A.C.; Lorincz, M.L.; Gould, T.M.; Carter, D.A.; Crunelli, V. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat. Med. 2009, 15, 1392–1398. [Google Scholar] [CrossRef] [Green Version]
- Vignoli, A.; Savini, M.N.; Nowbut, M.S.; Peron, A.; Turner, K.; La Briola, F.; Canevini, M.P. Effectiveness and tolerability of antiepileptic drugs in 104 girls with Rett syndrome. Epilepsy Behav. 2017, 66, 27–33. [Google Scholar] [CrossRef]
- Dani, V.S.; Chang, Q.; Maffei, A.; Turrigiano, G.G.; Jaenisch, R.; Nelson, S.B. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl. Acad. Sci. USA 2005, 102, 12560–12565. [Google Scholar] [CrossRef]
- Zhang, L.; He, J.; Jugloff, D.G.; Eubanks, J.H. The MeCP2-null mouse hippocampus displays altered basal inhibitory rhythms and is prone to hyperexcitability. Hippocampus 2008, 18, 294–309. [Google Scholar] [CrossRef] [PubMed]
- Calfa, G.; Hablitz, J.J.; Pozzo-Miller, L. Network hyperexcitability in hippocampal slices from Mecp2 mutant mice revealed by voltage-sensitive dye imaging. J. Neurophysiol. 2011, 105, 1768–1784. [Google Scholar] [CrossRef] [PubMed]
- Russell, J.C.; Blue, M.E.; Johnston, M.V.; Naidu, S.; Hossain, M.A. Enhanced cell death in MeCP2 null cerebellar granule neurons exposed to excitotoxicity and hypoxia. Neuroscience 2007, 150, 563–574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fischer, M.; Reuter, J.; Gerich, F.J.; Hildebrandt, B.; Hagele, S.; Katschinski, D.; Muller, M. Enhanced hypoxia susceptibility in hippocampal slices from a mouse model of rett syndrome. J. Neurophysiol. 2009, 101, 1016–1032. [Google Scholar] [CrossRef] [PubMed]
- Holmes, G.L. Models for generalized seizures. Suppl. Clin. Neurophysiol. 2004, 57, 415–424. [Google Scholar]
- Ben-Ari, Y.; Holmes, G.L. Effects of seizures on developmental processes in the immature brain. Lancet Neurol. 2006, 5, 1055–1063. [Google Scholar] [CrossRef]
- Karnam, H.B.; Zhao, Q.; Shatskikh, T.; Holmes, G.L. Effect of age on cognitive sequelae following early life seizures in rats. Epilepsy Res. 2009, 85, 221–230. [Google Scholar] [CrossRef] [Green Version]
- Karnam, H.B.; Zhou, J.L.; Huang, L.T.; Zhao, Q.; Shatskikh, T.; Holmes, G.L. Early life seizures cause long-standing impairment of the hippocampal map. Exp. Neurol. 2009, 217, 378–387. [Google Scholar] [CrossRef] [Green Version]
- Fuchs, C.; Medici, G.; Trazzi, S.; Gennaccaro, L.; Galvani, G.; Berteotti, C.; Ren, E.; Loi, M.; Ciani, E. CDKL5 deficiency predisposes neurons to cell death through the deregulation of SMAD3 signaling. Brain Pathol. 2019. [Google Scholar] [CrossRef]
- Chao, H.T.; Chen, H.; Samaco, R.C.; Xue, M.; Chahrour, M.; Yoo, J.; Neul, J.L.; Gong, S.; Lu, H.C.; Heintz, N.; et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 2010, 468, 263–269. [Google Scholar] [CrossRef]
- Krishnan, K.; Wang, B.S.; Lu, J.; Wang, L.; Maffei, A.; Cang, J.; Huang, Z.J. MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc. Natl. Acad. Sci. USA 2015, 112, E4782–E4791. [Google Scholar] [CrossRef]
- Zhang, Z.W.; Zak, J.D.; Liu, H. MeCP2 is required for normal development of GABAergic circuits in the thalamus. J. Neurophysiol. 2010, 103, 2470–2481. [Google Scholar] [CrossRef] [PubMed]
- Zerucha, T.; Stuhmer, T.; Hatch, G.; Park, B.K.; Long, Q.; Yu, G.; Gambarotta, A.; Schultz, J.R.; Rubenstein, J.L.; Ekker, M. A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain. J. Neurosci. 2000, 20, 709–721. [Google Scholar] [CrossRef] [PubMed]
- Horike, S.; Cai, S.; Miyano, M.; Cheng, J.F.; Kohwi-Shigematsu, T. Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat. Genet. 2005, 37, 31–40. [Google Scholar] [CrossRef] [PubMed]
- Kang, S.K.; Kim, S.T.; Johnston, M.V.; Kadam, S.D. Temporal- and Location-Specific Alterations of the GABA Recycling System in Mecp2 KO Mouse Brains. J. Cent. Nerv. Syst. Dis. 2014, 6, 21–28. [Google Scholar] [CrossRef] [PubMed]
- Ito-Ishida, A.; Ure, K.; Chen, H.; Swann, J.W.; Zoghbi, H.Y. Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes. Neuron 2015, 88, 651–658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- He, L.J.; Liu, N.; Cheng, T.L.; Chen, X.J.; Li, Y.D.; Shu, Y.S.; Qiu, Z.L.; Zhang, X.H. Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity. Nat. Commun. 2014, 5, 5036. [Google Scholar] [CrossRef]
- Morello, N.; Schina, R.; Pilotto, F.; Phillips, M.; Melani, R.; Plicato, O.; Pizzorusso, T.; Pozzo-Miller, L.; Giustetto, M. Loss of Mecp2 Causes Atypical Synaptic and Molecular Plasticity of Parvalbumin-Expressing Interneurons Reflecting Rett Syndrome-Like Sensorimotor Defects. eNeuro 2018, 24. [Google Scholar] [CrossRef]
- Demarest, S.; Pestana-Knight, E.M.; Olson, H.E.; Downs, J.; Marsh, E.D.; Kaufmann, W.E.; Partridge, C.A.; Leonard, H.; Gwadry-Sridhar, F.; Frame, K.E.; et al. Severity Assessment in CDKL5 Deficiency Disorder. Pediatr. Neurol. 2019, 97, 38–42. [Google Scholar] [CrossRef] [Green Version]
- Rose, S.A.; Wass, S.; Jankowski, J.J.; Feldman, J.F.; Djukic, A. Attentional shifting and disengagement in Rett syndrome. Neuropsychology 2019, 33, 335–342. [Google Scholar] [CrossRef]
- LeBlanc, J.J.; DeGregorio, G.; Centofante, E.; Vogel-Farley, V.K.; Barnes, K.; Kaufmann, W.E.; Fagiolini, M.; Nelson, C.A. Visual evoked potentials detect cortical processing deficits in Rett syndrome. Ann. Neurol. 2015, 78, 775–786. [Google Scholar] [CrossRef]
- Patrizi, A.; Picard, N.; Simon, A.J.; Gunner, G.; Centofante, E.; Andrews, N.A.; Fagiolini, M. Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype. Biol. Psychiatry 2016, 79, 755–764. [Google Scholar] [CrossRef] [PubMed]
- Patrizi, A.; Awad, P.N.; Chattopadhyaya, B.; Li, C.; Di Cristo, G.; Fagiolini, M. Accelerated Hyper-Maturation of Parvalbumin Circuits in the Absence of MeCP2. Cereb. Cortex 2019. [Google Scholar] [CrossRef] [PubMed]
- Mierau, S.B.; Patrizi, A.; Hensch, T.K.; Fagiolini, M. Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits. Biol. Psychiatry 2016, 79, 746–754. [Google Scholar] [CrossRef] [PubMed]
- Pizzo, R.; Gurgone, A.; Castroflorio, E.; Amendola, E.; Gross, C.; Sassoe-Pognetto, M.; Giustetto, M. Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex. Front. Cell. Neurosci. 2016, 10, 261. [Google Scholar] [CrossRef]
- Lunden, J.W.; Durens, M.; Phillips, A.W.; Nestor, M.W. Cortical interneuron function in autism spectrum condition. Pediatr. Res. 2019, 85, 146–154. [Google Scholar] [CrossRef]
- Takano, T. Interneuron Dysfunction in Syndromic Autism: Recent Advances. Dev. Neurosci. 2015, 37, 467–475. [Google Scholar] [CrossRef]
- Lioy, D.T.; Garg, S.K.; Monaghan, C.E.; Raber, J.; Foust, K.D.; Kaspar, B.K.; Hirrlinger, P.G.; Kirchhoff, F.; Bissonnette, J.M.; Ballas, N.; et al. A role for glia in the progression of Rett’s syndrome. Nature 2011, 475, 497–500. [Google Scholar] [CrossRef]
- Nguyen, M.V.; Du, F.; Felice, C.A.; Shan, X.; Nigam, A.; Mandel, G.; Robinson, J.K.; Ballas, N. MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. J. Neurosci. 2012, 32, 10021–10034. [Google Scholar] [CrossRef]
- Rakela, B.; Brehm, P.; Mandel, G. Astrocytic modulation of excitatory synaptic signaling in a mouse model of Rett syndrome. Elife 2018, 7. [Google Scholar] [CrossRef]
- Barres, B.A. The mystery and magic of glia: A perspective on their roles in health and disease. Neuron 2008, 60, 430–440. [Google Scholar] [CrossRef]
- Kahanovitch, U.; Cuddapah, V.A.; Pacheco, N.L.; Holt, L.M.; Mulkey, D.K.; Percy, A.K.; Olsen, M.L. MeCP2 Deficiency Leads to Loss of Glial Kir4.1. eNeuro 2018, 5. [Google Scholar] [CrossRef] [PubMed]
- Kahanovitch, U.; Patterson, K.C.; Hernandez, R.; Olsen, M.L. Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome. Int. J. Mol. Sci. 2019, 20, 3813. [Google Scholar] [CrossRef] [PubMed]
- Lee, H.S.; Ghetti, A.; Pinto-Duarte, A.; Wang, X.; Dziewczapolski, G.; Galimi, F.; Huitron-Resendiz, S.; Pina-Crespo, J.C.; Roberts, A.J.; Verma, I.M.; et al. Astrocytes contribute to gamma oscillations and recognition memory. Proc. Natl. Acad. Sci. USA 2014, 111, E3343–E3352. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moretti, P.; Bouwknecht, J.A.; Teague, R.; Paylor, R.; Zoghbi, H.Y. Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome. Hum. Mol. Genet. 2005, 14, 205–220. [Google Scholar] [CrossRef] [PubMed]
- De Filippis, B.; Fabbri, A.; Simone, D.; Canese, R.; Ricceri, L.; Malchiodi-Albedi, F.; Laviola, G.; Fiorentini, C. Modulation of RhoGTPases improves the behavioral phenotype and reverses astrocytic deficits in a mouse model of Rett syndrome. Neuropsychopharmacology 2012, 37, 1152–1163. [Google Scholar] [CrossRef] [PubMed]
- De Filippis, B.; Valenti, D.; Chiodi, V.; Ferrante, A.; de Bari, L.; Fiorentini, C.; Domenici, M.R.; Ricceri, L.; Vacca, R.A.; Fabbri, A.; et al. Modulation of Rho GTPases rescues brain mitochondrial dysfunction, cognitive deficits and aberrant synaptic plasticity in female mice modeling Rett syndrome. Eur. Neuropsychopharmacol. 2015, 25, 889–901. [Google Scholar] [CrossRef]
- Vigli, D.; Rusconi, L.; Valenti, D.; La Montanara, P.; Cosentino, L.; Lacivita, E.; Leopoldo, M.; Amendola, E.; Gross, C.; Landsberger, N.; et al. Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder. Neuropharmacology 2019, 144, 104–114. [Google Scholar] [CrossRef]
- Sohal, V.S.; Zhang, F.; Yizhar, O.; Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 2009, 459, 698–702. [Google Scholar] [CrossRef] [Green Version]
- Sun, Y.; Gao, Y.; Tidei, J.J.; Shen, M.; Hoang, J.T.; Wagner, D.F.; Zhao, X. Loss of MeCP2 in immature neurons leads to impaired network integration. Hum. Mol. Genet. 2019, 28, 245–257. [Google Scholar] [CrossRef]
- Wang, I.T.; Allen, M.; Goffin, D.; Zhu, X.; Fairless, A.H.; Brodkin, E.S.; Siegel, S.J.; Marsh, E.D.; Blendy, J.A.; Zhou, Z. Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice. Proc. Natl. Acad. Sci. USA 2012, 109, 21516–21521. [Google Scholar] [CrossRef] [Green Version]
- Doyon, N.; Vinay, L.; Prescott, S.A.; De Koninck, Y. Cl- Regulation: A Dynamic Equilibrium Crucial for Synaptic Inhibition. Neuron 2016, 89, 1157–1172. [Google Scholar] [CrossRef] [PubMed]
- Young, D.; Nagarajan, L.; de Klerk, N.; Jacoby, P.; Ellaway, C.; Leonard, H. Sleep problems in Rett syndrome. Brain Dev. 2007, 29, 609–616. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wong, K.; Leonard, H.; Jacoby, P.; Ellaway, C.; Downs, J. The trajectories of sleep disturbances in Rett syndrome. J. Sleep Res. 2015, 24, 223–233. [Google Scholar] [CrossRef] [PubMed]
- Boban, S.; Leonard, H.; Wong, K.; Wilson, A.; Downs, J. Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices. Am. J. Med. Genet. A 2018, 176, 1569–1577. [Google Scholar] [CrossRef]
- Malow, B.A. Sleep deprivation and epilepsy. Epilepsy Curr. 2004, 4, 193–195. [Google Scholar] [CrossRef]
- Shahbazian, M.; Young, J.; Yuva-Paylor, L.; Spencer, C.; Antalffy, B.; Noebels, J.; Armstrong, D.; Paylor, R.; Zoghbi, H. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 2002, 35, 243–254. [Google Scholar] [CrossRef]
- Lawson-Yuen, A.; Liu, D.; Han, L.; Jiang, Z.I.; Tsai, G.E.; Basu, A.C.; Picker, J.; Feng, J.; Coyle, J.T. Ube3a mRNA and protein expression are not decreased in Mecp2R168X mutant mice. Brain Res. 2007, 1180, 1–6. [Google Scholar] [CrossRef] [Green Version]
- Lappalainen, R.; Liewendahl, K.; Sainio, K.; Nikkinen, P.; Riikonen, R.S. Brain perfusion SPECT and EEG findings in Rett syndrome. Acta Neurol. Scand. 1997, 95, 44–50. [Google Scholar] [CrossRef]
- Ammanuel, S.; Chan, W.C.; Adler, D.A.; Lakshamanan, B.M.; Gupta, S.S.; Ewen, J.B.; Johnston, M.V.; Marcus, C.L.; Naidu, S.; Kadam, S.D. Heightened Delta Power during Slow-Wave-Sleep in Patients with Rett Syndrome Associated with Poor Sleep Efficiency. PLoS ONE 2015, 10, e0138113. [Google Scholar] [CrossRef]
- Blue, M.E.; Naidu, S.; Johnston, M.V. Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome. Exp. Neurol. 1999, 156, 345–352. [Google Scholar] [CrossRef]
- Mangatt, M.; Wong, K.; Anderson, B.; Epstein, A.; Hodgetts, S.; Leonard, H.; Downs, J. Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet J. Rare Dis. 2016, 11, 39. [Google Scholar] [CrossRef] [PubMed]
- Hagebeuk, E.E.; Duran, M.; Abeling, N.G.; Vyth, A.; Poll-The, B.T. S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation. J. Inherit. Metab. Dis. 2013, 36, 967–972. [Google Scholar] [CrossRef] [PubMed]
- Lo Martire, V.; Alvente, S.; Bastianini, S.; Berteotti, C.; Silvani, A.; Valli, A.; Viggiano, R.; Ciani, E.; Zoccoli, G. CDKL5 deficiency entails sleep apneas in mice. J. Sleep Res. 2017, 26, 495–497. [Google Scholar] [CrossRef] [PubMed]
- Katz, D.M.; Berger-Sweeney, J.E.; Eubanks, J.H.; Justice, M.J.; Neul, J.L.; Pozzo-Miller, L.; Blue, M.E.; Christian, D.; Crawley, J.N.; Giustetto, M.; et al. Preclinical research in Rett syndrome: Setting the foundation for translational success. Dis. Models Mech. 2012, 5, 733–745. [Google Scholar] [CrossRef]
- Ricceri, L.; De Filippis, B.; Laviola, G. Rett syndrome treatment in mouse models: Searching for effective targets and strategies. Neuropharmacology 2013, 68, 106–115. [Google Scholar] [CrossRef]
- Chapleau, C.A.; Lane, J.; Larimore, J.; Li, W.; Pozzo-Miller, L.; Percy, A.K. Recent Progress in Rett Syndrome and MeCP2 Dysfunction: Assessment of Potential Treatment Options. Future Neurol. 2013, 8. [Google Scholar] [CrossRef]
- Pozzo-Miller, L.; Pati, S.; Percy, A.K. Rett Syndrome: Reaching for Clinical Trials. Neurotherapeutics 2015, 12, 631–640. [Google Scholar] [CrossRef] [Green Version]
- Katz, D.M.; Bird, A.; Coenraads, M.; Gray, S.J.; Menon, D.U.; Philpot, B.D.; Tarquinio, D.C. Rett Syndrome: Crossing the Threshold to Clinical Translation. Trends Neurosci. 2016, 39, 100–113. [Google Scholar] [CrossRef] [Green Version]
- Horska, A.; Farage, L.; Bibat, G.; Nagae, L.M.; Kaufmann, W.E.; Barker, P.B.; Naidu, S. Brain metabolism in Rett syndrome: Age, clinical, and genotype correlations. Ann. Neurol. 2009, 65, 90–97. [Google Scholar] [CrossRef]
- Kron, M.; Howell, C.J.; Adams, I.T.; Ransbottom, M.; Christian, D.; Ogier, M.; Katz, D.M. Brain Activity Mapping in Mecp2 Mutant Mice Reveals Functional Deficits in Forebrain Circuits, Including Key Nodes in the Default Mode Network, that are Reversed with Ketamine Treatment. J. Neurosci. 2012, 32, 13860–13872. [Google Scholar] [CrossRef] [Green Version]
- Weng, S.M.; McLeod, F.; Bailey, M.E.; Cobb, S.R. Synaptic plasticity deficits in an experimental model of rett syndrome: Long-term potentiation saturation and its pharmacological reversal. Neuroscience 2011, 180, 314–321. [Google Scholar] [CrossRef] [PubMed]
- Gogliotti, R.G.; Senter, R.K.; Rook, J.M.; Ghoshal, A.; Zamorano, R.; Malosh, C.; Stauffer, S.R.; Bridges, T.M.; Bartolome, J.M.; Daniels, J.S.; et al. mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome. Hum. Mol. Genet. 2016, 25, 1990–2004. [Google Scholar] [CrossRef] [PubMed]
- Tao, J.; Wu, H.; Coronado, A.A.; de Laittre, E.; Osterweil, E.K.; Zhang, Y.; Bear, M.F. Negative Allosteric Modulation of mGluR5 Partially Corrects Pathophysiology in a Mouse Model of Rett Syndrome. J. Neurosci. 2016, 36, 11946–11958. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dalezios, Y.; Lujan, R.; Shigemoto, R.; Roberts, J.D.; Somogyi, P. Enrichment of mGluR7a in the presynaptic active zones of GABAergic and non-GABAergic terminals on interneurons in the rat somatosensory cortex. Cereb. Cortex 2002, 12, 961–974. [Google Scholar] [CrossRef] [PubMed]
- Gogliotti, R.G.; Senter, R.K.; Fisher, N.M.; Adams, J.; Zamorano, R.; Walker, A.G.; Blobaum, A.L.; Engers, D.W.; Hopkins, C.R.; Daniels, J.S.; et al. mGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome. Sci. Transl. Med. 2017, 9. [Google Scholar] [CrossRef]
- Linge, R.; Jimenez-Sanchez, L.; Campa, L.; Pilar-Cuellar, F.; Vidal, R.; Pazos, A.; Adell, A.; Diaz, A. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: Role of 5-HT1A receptors. Neuropharmacology 2016, 103, 16–26. [Google Scholar] [CrossRef] [PubMed]
- Lahmy, V.; Long, R.; Morin, D.; Villard, V.; Maurice, T. Mitochondrial protection by the mixed muscarinic/sigma1 ligand ANAVEX2–73, a tetrahydrofuran derivative, in Abeta25–35 peptide-injected mice, a nontransgenic Alzheimer’s disease model. Front. Cell. Neurosci. 2014, 8, 463. [Google Scholar] [CrossRef]
- Park, M.J.; Aja, S.; Li, Q.; Degano, A.L.; Penati, J.; Zhuo, J.; Roe, C.R.; Ronnett, G.V. Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice. PLoS ONE 2014, 9, e109527. [Google Scholar] [CrossRef]
- Tropea, D.; Mortimer, N.; Bellini, S.; Molinos, I.; Sanfeliu, A.; Shovlin, S.; McAllister, D.; Gill, M.; Mitchell, K.; Corvin, A. Expression of nuclear Methyl-CpG binding protein 2 (Mecp2) is dependent on neuronal stimulation and application of Insulin-like growth factor 1. Neurosci. Lett. 2016, 621, 111–116. [Google Scholar] [CrossRef]
- Glaze, D.G.; Neul, J.L.; Percy, A.; Feyma, T.; Beisang, A.; Yaroshinsky, A.; Stoms, G.; Zuchero, D.; Horrigan, J.; Glass, L.; et al. A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome. Pediatr. Neurol. 2017, 76, 37–46. [Google Scholar] [CrossRef]
- Glaze, D.G.; Neul, J.L.; Kaufmann, W.E.; Berry-Kravis, E.; Condon, S.; Stoms, G.; Oosterholt, S.; Della Pasqua, O.; Glass, L.; Jones, N.E.; et al. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology 2019, 92, e1912–e1925. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gasior, M.; Carter, R.B.; Goldberg, S.R.; Witkin, J.M. Anticonvulsant and behavioral effects of neuroactive steroids alone and in conjunction with diazepam. J. Pharm. Exp. 1997, 282, 543–553. [Google Scholar]
- Carter, R.B.; Wood, P.L.; Wieland, S.; Hawkinson, J.E.; Belelli, D.; Lambert, J.J.; White, H.S.; Wolf, H.H.; Mirsadeghi, S.; Tahir, S.H.; et al. Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor. J. Pharm. Exp. 1997, 280, 1284–1295. [Google Scholar]
- Miller, J.N.; Kovacs, A.D.; Pearce, D.A. The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum. Mol. Genet. 2015, 24, 185–196. [Google Scholar] [CrossRef] [PubMed]
- Schoonjans, A.; Paelinck, B.P.; Marchau, F.; Gunning, B.; Gammaitoni, A.; Galer, B.S.; Lagae, L.; Ceulemans, B. Low-dose fenfluramine significantly reduces seizure frequency in Dravet syndrome: A prospective study of a new cohort of patients. Eur. J. Neurol. 2017, 24, 309–314. [Google Scholar] [CrossRef] [PubMed]
- Dinday, M.T.; Baraban, S.C. Large-Scale Phenotype-Based Antiepileptic Drug Screening in a Zebrafish Model of Dravet Syndrome. eNeuro 2015, 2. [Google Scholar] [CrossRef]
- Rodriguez-Munoz, M.; Sanchez-Blazquez, P.; Garzon, J. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget 2018, 9, 23373–23389. [Google Scholar] [CrossRef] [Green Version]
- Sodero, A.O.; Vriens, J.; Ghosh, D.; Stegner, D.; Brachet, A.; Pallotto, M.; Sassoe-Pognetto, M.; Brouwers, J.F.; Helms, J.B.; Nieswandt, B.; et al. Cholesterol loss during glutamate-mediated excitotoxicity. EMBO J. 2012, 31, 1764–1773. [Google Scholar] [CrossRef] [Green Version]
- Paul, S.M.; Doherty, J.J.; Robichaud, A.J.; Belfort, G.M.; Chow, B.Y.; Hammond, R.S.; Crawford, D.C.; Linsenbardt, A.J.; Shu, H.J.; Izumi, Y.; et al. The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors. J. Neurosci. 2013, 33, 17290–17300. [Google Scholar] [CrossRef]
- Hagebeuk, E.E.; Duran, M.; Koelman, J.H.; Abeling, N.G.; Vyth, A.; Poll-The, B.T. Folinic acid supplementation in Rett syndrome patients does not influence the course of the disease: A randomized study. J. Child. Neurol. 2012, 27, 304–309. [Google Scholar] [CrossRef]
- Cosentino, L.; Vigli, D.; Franchi, F.; Laviola, G.; De Filippis, B. Rett syndrome before regression: A time window of overlooked opportunities for diagnosis and intervention. Neurosci. Biobehav. Rev. 2019, 107, 115–135. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.; Bedogni, F.; Boterberg, S.; Camfield, C.; Camfield, P.; Charman, T.; Curfs, L.; Einspieler, C.; Esposito, G.; De Filippis, B.; et al. Towards a consensus on developmental regression. Neurosci. Biobehav. Rev. 2019, 107, 3–5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Srivastava, S.; Desai, S.; Cohen, J.; Smith-Hicks, C.; Baranano, K.; Fatemi, A.; Naidu, S. Monogenic disorders that mimic the phenotype of Rett syndrome. Neurogenetics 2018, 19, 41–47. [Google Scholar] [CrossRef] [PubMed]
- Neul, J.L. Can Rett syndrome be diagnosed before regression? Neurosci. Biobehav. Rev. 2019, 104, 158–159. [Google Scholar] [CrossRef] [PubMed]
- Smith-Hicks, C.L.; Gupta, S.; Ewen, J.B.; Hong, M.; Kratz, L.; Kelley, R.; Tierney, E.; Vaurio, R.; Bibat, G.; Sanyal, A.; et al. Randomized open-label trial of dextromethorphan in Rett syndrome. Neurology 2017, 89, 1684–1690. [Google Scholar] [CrossRef]
- Rose, S.A.; Djukic, A.; Jankowski, J.J.; Feldman, J.F.; Fishman, I.; Valicenti-McDermott, M. Rett syndrome: An eye-tracking study of attention and recognition memory. Dev. Med. Child. Neurol. 2013, 55, 364–371. [Google Scholar] [CrossRef]
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kadam, S.D.; Sullivan, B.J.; Goyal, A.; Blue, M.E.; Smith-Hicks, C. Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic. Int. J. Mol. Sci. 2019, 20, 5098. https://doi.org/10.3390/ijms20205098
Kadam SD, Sullivan BJ, Goyal A, Blue ME, Smith-Hicks C. Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic. International Journal of Molecular Sciences. 2019; 20(20):5098. https://doi.org/10.3390/ijms20205098
Chicago/Turabian StyleKadam, Shilpa D., Brennan J. Sullivan, Archita Goyal, Mary E. Blue, and Constance Smith-Hicks. 2019. "Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic" International Journal of Molecular Sciences 20, no. 20: 5098. https://doi.org/10.3390/ijms20205098