Global brain delivery of neuroligin 2 gene ameliorates seizures in a mouse model of epilepsy.
EL mouse
adeno-associated virus
epilepsy
gene therapy
neuroligin 2
Journal
The journal of gene medicine
ISSN: 1521-2254
Titre abrégé: J Gene Med
Pays: England
ID NLM: 9815764
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
revised:
29
11
2021
received:
07
09
2021
accepted:
02
12
2021
pubmed:
14
12
2021
medline:
21
4
2022
entrez:
13
12
2021
Statut:
ppublish
Résumé
Despite the increasing availability of effective drugs, around one-third of patients with epilepsy are still resistant to pharmacotherapy. Gene therapy has been suggested as a plausible approach to achieve seizure control, in particular for patients with focal epilepsy. Because seizures develop across wide spans of the brain in many forms of epilepsy, global delivery of the vectors is necessary to tackle such generalized seizures. Neuroligin 2 (NL2) is a postsynaptic cell adhesion molecule that induces or strengthens inhibitory synaptic function by specifically combining with neurexin 1. In the present study, we applied an adeno-associated virus (AAV) type 9 vector expressing NL2 to modulate neuronal excitability in broad areas of the brain in epileptic (EL) mice, a model of polygene epilepsy. We administered the AAV vector expressing Flag-tagged NL2 under the synapsin I promoter (AAV-NL2) via cardiac injection 6 weeks after birth. Significant reductions in the duration, strength and frequency of seizure were observed during a 14-week observation period in NL2-treated EL mice compared to untreated or AAV-green fluorescent protein-treated EL mice. No behavioral abnormality was observed in NL2-treated EL mice in an open-field test. Immunohistochemical examination at 14 weeks after AAV-NL2 injection revealed the expression of exogenous NL2 in broad areas of the brain, including the hippocampus and, in these areas, NL2 co-localized with postsynaptic inhibitory molecule gephyrin. Global brain delivery of NL2 by systemic administration of AAV vector may provide a non-invasive therapeutic approach for generalized epilepsy.
Sections du résumé
BACKGROUND
Despite the increasing availability of effective drugs, around one-third of patients with epilepsy are still resistant to pharmacotherapy. Gene therapy has been suggested as a plausible approach to achieve seizure control, in particular for patients with focal epilepsy. Because seizures develop across wide spans of the brain in many forms of epilepsy, global delivery of the vectors is necessary to tackle such generalized seizures. Neuroligin 2 (NL2) is a postsynaptic cell adhesion molecule that induces or strengthens inhibitory synaptic function by specifically combining with neurexin 1.
METHODS
In the present study, we applied an adeno-associated virus (AAV) type 9 vector expressing NL2 to modulate neuronal excitability in broad areas of the brain in epileptic (EL) mice, a model of polygene epilepsy. We administered the AAV vector expressing Flag-tagged NL2 under the synapsin I promoter (AAV-NL2) via cardiac injection 6 weeks after birth.
RESULTS
Significant reductions in the duration, strength and frequency of seizure were observed during a 14-week observation period in NL2-treated EL mice compared to untreated or AAV-green fluorescent protein-treated EL mice. No behavioral abnormality was observed in NL2-treated EL mice in an open-field test. Immunohistochemical examination at 14 weeks after AAV-NL2 injection revealed the expression of exogenous NL2 in broad areas of the brain, including the hippocampus and, in these areas, NL2 co-localized with postsynaptic inhibitory molecule gephyrin.
CONCLUSIONS
Global brain delivery of NL2 by systemic administration of AAV vector may provide a non-invasive therapeutic approach for generalized epilepsy.
Substances chimiques
Cell Adhesion Molecules, Neuronal
0
Nerve Tissue Proteins
0
neuroligin 2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3402Informations de copyright
© 2021 John Wiley & Sons, Ltd.
Références
Fisher RS, van Emde BW, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46(4):470-472.
Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314-319.
Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365(10):919-926.
Picot MC, Baldy-Moulinier M, Daures JP, Dujols P, Crespel A. The prevalence of epilepsy and pharmacoresistant epilepsy in adults: a population-based study in a Western European country. Epilepsia. 2008;49(7):1230-1238.
Chen B, Choi H, Hirsch LJ, et al. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2017;76:24-31.
Kaushik S, Chopra D, Sharma S, Aneja S. Adverse drug reactions of anti-epileptic drugs in children with epilepsy: a cross-sectional study. Curr Drug Saf. 2019;14(3):217-224.
Schuele SU, Lüders HO. Intractable epilepsy: management and therapeutic alternatives. The Lancet Neurology. 2008;7:(6):514-524. https://doi.org/10.1016/s1474-4422(08)70108-x
González HFJ, Yengo-Kahn A, Englot DJ. Vagus nerve stimulation for the treatment of epilepsy. Neurosurg Clin N Am. 2019;30(2):219-230.
Morris GL 3rd, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology. 1999;53(8):1731-1735.
Li MCH, Cook MJ. Deep brain stimulation for drug-resistant epilepsy. Epilepsia. 2018;59(2):273-290.
Van Dycke A, Raedt R, Vonck K, Boon P. Local delivery strategies in epilepsy: a focus on adenosine. Seizure. 2011;20(5):376-382.
Csernyus B, Szabó Á, Zátonyi A, et al. Recent antiepileptic and neuroprotective applications of brain cooling. Seizure. 2020;82:80-90.
Hunt RF, Baraban SC. Interneuron Transplantation as a Treatment for Epilepsy. Cold Spring Harbor Perspectives in Medicine. 2015;5:(12):a022376. https://doi.org/10.1101/cshperspect.a022376
Agostinho AS, Mietzsch M, Zangrandi L, et al. Dynorphin-based “release on demand” gene therapy for drug-resistant temporal lobe epilepsy. EMBO Molecular Medicine. 2019;11:(10):e9963. https://doi.org/10.15252/emmm.201809963
George S, James S, De Blas AL. Selective Overexpression of Collybistin in Mouse Hippocampal Pyramidal Cells Enhances GABAergic Neurotransmission and Protects against PTZ-Induced Seizures. eneuro. 2021;8:(4):ENEURO.0561-20.2021. https://doi.org/10.1523/eneuro.0561-20.2021
Lieb A, Qiu Y, Dixon CL, et al. Biochemical autoregulatory gene therapy for focal epilepsy. Nat Med. 2018;24(9):1324-1329.
Melin E, Nanobashvili A, Avdic U, et al. Disease modification by combinatorial single vector gene therapy: a preclinical translational study in epilepsy. Mol Ther Methods Clin Dev. 2019;15:179-193.
Shimazaki K, Kobari T, Oguro K, et al. Hippocampal GAD67 transduction using rAAV8 regulates epileptogenesis in EL mice. Mol Ther Methods Clin Dev. 2019;13:180-186.
Snowball A, Chabrol E, Wykes RC, et al. Epilepsy gene therapy using an engineered potassium channel. J Neurosci. 2019;39(16):3159-3169.
Bottos A, Rissone A, Bussolino F, Arese M. Neurexins and neuroligins: synapses look out of the nervous system. Cell Mol Life Sci. 2011;68(16):2655-2666.
Dalva MB, McClelland AC, Kayser MS. Cell adhesion molecules: signalling functions at the synapse. Nat Rev Neurosci. 2007;8(3):206-220.
Krueger DD, Tuffy LP, Papadopoulos T, Brose N. The role of neurexins and neuroligins in the formation, maturation, and function of vertebrate synapses. Curr Opin Neurobiol. 2012;22(3):412-422.
Bolliger MF, Frei K, Winterhalter KH, Gloor SM. Identification of a novel neuroligin in humans which binds to PSD-95 and has a widespread expression. Biochem J. 2001;356(Pt 2):581-588.
Ichtchenko K, Hata Y, Nguyen T, et al. Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell. 1995;81(3):435-443.
Ali H, Marth L, Krueger-Burg D. Neuroligin-2 as a central organizer of inhibitory synapses in health and disease. Science Signaling. 2020;13:(663):eabd8379. https://doi.org/10.1126/scisignal.abd8379
Chubykin AA, Atasoy D, Etherton MR, et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron. 2007;54(6):919-931.
Varoqueaux F, Jamain S, Brose N. Neuroligin 2 is exclusively localized to inhibitory synapses. Eur J Cell Biol. 2004;83(9):449-456.
Iida A, Takino N, Miyauchi H, Shimazaki K, Muramatsu S. Systemic Delivery of Tyrosine-Mutant AAV Vectors Results in Robust Transduction of Neurons in Adult Mice. BioMed Research International. 2013;2013:1-8. https://doi.org/10.1155/2013/974819
Lee NC, Muramatsu S, Chien YH, et al. Benefits of neuronal preferential systemic gene therapy for neurotransmitter deficiency. Mol Ther. 2015;23(10):1572-1581.
Yamashita T, Chai HL, Teramoto S, et al. Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons. EMBO Mol Med. 2013;5(11):1710-1719.
Murashima YL, Kassamo K, Suzuki J. Developmental and seizure-related regional differences in immediate early gene expression and GABAergic abnormalities in the brain of EL mice. Epilepsy Res. 1996;26(1):3-14.
Suzuki J. Neuronal mechanism of epileptogenesis in EL mouse. Proc Jpn Acad Ser B Phys Biol Sci. 2013;89(6):270-280.
Gao G, Vandenberghe LH, Alvira MR, et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J Virol. 2004;78(12):6381-6388.
Petrs-Silva H, Dinculescu A, Li Q, et al. Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina. Mol Ther. 2011;19(2):293-301.
Cramer JA. Assessing the severity of seizures and epilepsy: which scales are valid? Curr Opin Neurol. 2001;14(2):225-229.
Cramer JA, French J. Quantitative assessment of seizure severity for clinical trials: a review of approaches to seizure components. Epilepsia. 2001;42(1):119-129.
Parente DJ, Garriga C, Baskin B, et al. Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity. Am J Med Genet a. 2017;173(1):213-216.
Chien YH, Lee NC, Tseng SH, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. 2017;1(4):265-273.
Kojima K, Nakajima T, Taga N, et al. Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency. Brain. 2019;142(2):322-333.
Muramatsu S, Fujimoto K, Kato S, et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease. Mol Ther. 2010;18(9):1731-1735.
Niethammer M, Tang CC, LeWitt PA, et al. Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease. JCI Insight. 2017;2:(7):e90133. https://doi.org/10.1172/jci.insight.90133
Sehara Y, Fujimoto KI, Ikeguchi K, et al. Persistent expression of dopamine-synthesizing enzymes 15 years after gene transfer in a primate model of Parkinson's disease. Hum Gene Ther Clin Dev. 2017;28(2):74-79.
Muramatsu S, Mizukami H, Young NS, Brown KE. Nucleotide sequencing and generation of an infectious clone of adeno-associated virus 3. Virology. 1996;221(1):208-217.
Nakamura S, Osaka H, Muramatsu SI, et al. Intra-cisterna magna delivery of an AAV vector with the GLUT1 promoter in a pig recapitulates the physiological expression of SLC2A1. Gene Ther. 2021;28(6):329-338.
Seyfried TN, Glaser GH. A review of mouse mutants as genetic models of epilepsy. Epilepsia. 1985;26(2):143-150.
Ono T, Fueta Y, Janjua NA, et al. Granule cell disinhibition in dentate gyrus of genetically seizure susceptible El mice. Brain Res. 1997;745(1-2):165-172.
Van Zandt M, Weiss E, Almyasheva A, Lipior S, Maisel S, Naegele JR. Adeno-associated viral overexpression of neuroligin 2 in the mouse hippocampus enhances GABAergic synapses and impairs hippocampal-dependent behaviors. Behav Brain Res. 2019;362:7-20.
Heshmati M, Aleyasin H, Menard C, et al. Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proc Natl Acad Sci U S A. 2018;115(5):1111-1116.
Sun C, Cheng MC, Qin R, et al. Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. Hum Mol Genet. 2011;20(15):3042-3051.
Kohl C, Riccio O, Grosse J, et al. Hippocampal Neuroligin-2 Overexpression Leads to Reduced Aggression and Inhibited Novelty Reactivity in Rats. PLoS ONE. 2013;8:(2):e56871. https://doi.org/10.1371/journal.pone.0056871
Choleris E, Thomas AW, Kavaliers M, Prato FS. A detailed ethological analysis of the mouse open field test: effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic field. Neurosci Biobehav Rev. 2001;25(3):235-260.
Kuniishi H, Ichisaka S, Yamamoto M, et al. Early deprivation increases high-leaning behavior, a novel anxiety-like behavior, in the open field test in rats. Neurosci Res. 2017;123:27-35.
Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol. 2003;463(1-3):3-33.
Noe' FM, Sørensen AT, Kokaia M, Vezzani A. Gene therapy of focal onset epilepsy using adeno-associated virus vector-mediated overexpression of neuropeptide Y. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds. Jasper's Basic Mechanisms of the Epilepsies. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
Colasante G, Qiu Y, Massimino L, et al. In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy. Brain. 2020;143(3):891-905.