Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy
Childhood epilepsy syndromes, such as the early epileptic encephalopathies (EE’s) encompass seizure disorders that manifest early and negatively impact or completely block developmental progression. Recently, mutations in DNM1 (dynamin 1) have been implicated in two EE syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Dynamin 1 is a large multimeric protein that is critical for electro-chemical communication between neurons. To understand the relationship between severe seizures and the cognitive and behavioral developmental outcomes in DNM1 patients, we focus on “fitful” mice that carry a mutation in the dynamin 1 gene. Fitful mice have an EE disorder that is highly reminiscent of the documented human patients. Here, we describe genetic manipulations in the mice that allow us to determine that the seizure activity has independent cellular origins from the developmental and behavioral consequences. This separation confirms that the seizures do not cause the severe developmental delay and abnormal behaviors in this animal model and further suggests that any treatments aimed at controlling the seizures per se may not be effective for some of the most acute neurobehavioral symptoms in these patients.
Vyšlo v časopise:
Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005347
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1005347
Souhrn
Childhood epilepsy syndromes, such as the early epileptic encephalopathies (EE’s) encompass seizure disorders that manifest early and negatively impact or completely block developmental progression. Recently, mutations in DNM1 (dynamin 1) have been implicated in two EE syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Dynamin 1 is a large multimeric protein that is critical for electro-chemical communication between neurons. To understand the relationship between severe seizures and the cognitive and behavioral developmental outcomes in DNM1 patients, we focus on “fitful” mice that carry a mutation in the dynamin 1 gene. Fitful mice have an EE disorder that is highly reminiscent of the documented human patients. Here, we describe genetic manipulations in the mice that allow us to determine that the seizure activity has independent cellular origins from the developmental and behavioral consequences. This separation confirms that the seizures do not cause the severe developmental delay and abnormal behaviors in this animal model and further suggests that any treatments aimed at controlling the seizures per se may not be effective for some of the most acute neurobehavioral symptoms in these patients.
Zdroje
1. EuroEPINOMIC-RES Consortium EPGP, Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95: 360–370. doi: 10.1016/j.ajhg.2014.08.013 25262651
2. Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519: 223–228. doi: 10.1038/nature14135 25533962
3. Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501: 217–221. doi: 10.1038/nature12439 23934111
4. Dhindsa RS, Bradrick SS, Yao XY, Heinzen EL, Petrovski S, Krueger BJ, et al. Epileptic encephalopathy causing DNM1 mutations impair synaptic vesicle endocytosis. Neurol Genet. 2015;1: e4.
5. Boumil RM, Letts VA, Roberts MC, Lenz C, Mahaffey CL, Zhang ZW, et al. A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. PLoS Genet. 2010;6.
6. Ferguson SM, Brasnjo G, Hayashi M, Wolfel M, Collesi C, Giovedi S, et al. A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science. 2007;316: 570–574. 17463283
7. Ferguson SM, Raimondi A, Paradise S, Shen H, Mesaki K, Ferguson A, et al. Coordinated actions of actin and BAR proteins upstream of dynamin at endocytic clathrin-coated pits. Dev Cell. 2009;17: 811–822. doi: 10.1016/j.devcel.2009.11.005 20059951
8. van Rijckevorsel K. Cognitive problems related to epilepsy syndromes, especially malignant epilepsies. Seizure. 2006;15: 227–234. 16563807
9. Wagner GP, Zhang J. The pleiotropic structure of the genotype-phenotype map: the evolvability of complex organisms. Nat Rev Genet. 2011;12: 204–213. doi: 10.1038/nrg2949 21331091
10. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nature Neurosci. 2010;13: 133–140. doi: 10.1038/nn.2467 20023653
11. Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, et al. A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron. 2011;71: 995–1013. doi: 10.1016/j.neuron.2011.07.026 21943598
12. Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JL, Jones KR. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci. 2002;22: 6309–6314. 12151506
13. Hippenmeyer S, Vrieseling E, Sigrist M, Portmann T, Laengle C, Ladle DR, et al. A developmental switch in the response of DRG neurons to ETS transcription factor signaling. PLoS Biol. 2005;3: e159. 15836427
14. Potter GB, Petryniak MA, Shevchenko E, McKinsey GL, Ekker M, Rubenstein JL. Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneurons. Mol Cell Neurosci. 2009;40: 167–186. doi: 10.1016/j.mcn.2008.10.003 19026749
15. Bartos M, Vida I, Jonas P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nature Rev Neurosci. 2007;8: 45–56.
16. Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C. Interneurons of the neocortical inhibitory system. Nature Rev Neurosci. 2004;5: 793–807.
17. McBain CJ, Fisahn A. Interneurons unbound. Nature Rev Neurosci. 2001;2: 11–23.
18. Dutton SB, Makinson CD, Papale LA, Shankar A, Balakrishnan B, Nakazawa K, et al. Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility. Neurobiol Dis. 2012;49C: 211–220.
19. Rudy B, Fishell G, Lee S, Hjerling-Leffler J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol. 2010;71: 45–61.
20. Tolstykh GP, Cavazos JE. Potential mechanisms of sudden unexpected death in epilepsy. Epilepsy Behav. 2013;26: 410–414. doi: 10.1016/j.yebeh.2012.09.017 23305781
21. Monory K, Massa F, Egertova M, Eder M, Blaudzun H, Westenbroek R, et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron. 2006;51: 455–466. 16908411
22. Hayashi M, Raimondi A, O'Toole E, Paradise S, Collesi C, Cremona O, et al. Cell- and stimulus-dependent heterogeneity of synaptic vesicle endocytic recycling mechanisms revealed by studies of dynamin 1-null neurons. PNAS. 2008;105: 2175–2180. doi: 10.1073/pnas.0712171105 18250322
23. Brooks-Kayal A. Molecular mechanisms of cognitive and behavioral comorbidities of epilepsy in children. Epilepsia. 2011;52 Suppl 1: 13–20. doi: 10.1111/j.1528-1167.2010.02906.x 21214535
24. Nieh SE, Sherr EH. Epileptic encephalopathies: new genes and new pathways. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics. 2014;11: 796–806.
25. Pierce K, Courchesne E. Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol Psychiatry. 2001;49: 655–664. 11313033
26. World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders. Geneva, Switzerland.
27. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders. Washington D.C.
28. Ogiwara I, Iwasato T, Miyamoto H, Iwata R, Yamagata T, Mazaki E, et al. Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome. Hum Mol Gen. 2013;22: 4784–4804. doi: 10.1093/hmg/ddt331 23922229
29. Youssoufian H, Pyeritz RE. Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet. 2002;3: 748–758. 12360233
30. Mayorga AJ, Lucki I. Limitations on the use of the C57BL/6 mouse in the tail suspension test. Psychopharmacol (Berl). 2001;155: 110–112.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2015 Číslo 6
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Non-reciprocal Interspecies Hybridization Barriers in the Capsella Genus Are Established in the Endosperm
- Translational Upregulation of an Individual p21 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress
- Exome Sequencing of Phenotypic Extremes Identifies and as Interacting Modifiers of Chronic Infection in Cystic Fibrosis
- The Human Blood Metabolome-Transcriptome Interface