Hyperexcitability of the local cortical circuit in mouse models of tuberous sclerosis complex

Molecular Brain - Tập 12 - Trang 1-13 - 2019
Jian-Ping Zhao1,2, Akira Yoshii3,1,2
1Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, USA
2McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, USA
3Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, USA

Tóm tắt

Tuberous sclerosis complex (TSC) is a neurogenetic disorder associated with epilepsy, intellectual disabilities, and autistic behaviors. These neurological symptoms result from synaptic dysregulations, which shift a balance between excitation and inhibition. To decipher the synaptic substrate of hyperexcitability, we examined pan-neuronal Tsc1 knockout mouse and found a reduction in surface expression of a GABA receptor (GABAR) subunit but not AMPA receptor (AMPAR) subunit. Using electrophysiological recordings, we found a significant reduction in the frequency of GABAR-mediated miniature inhibitory postsynaptic currents (GABAR-mIPSCs) but not AMPAR-mediated miniature excitatory postsynaptic currents (AMPAR-mEPSCs) in layer 2/3 pyramidal neurons. To determine a subpopulation of interneurons that are especially vulnerable to the absence of TSC1 function, we also analyzed two strains of conditional knockout mice targeting two of the prominent interneuron subtypes that express parvalbumin (PV) or somatostatin (SST). Unlike pan-neuronal knockout mice, both interneuron-specific Tsc-1 knockout mice did not develop spontaneous seizures and grew into adults. Further, the properties of AMPAR-mEPSCs and GABAR-mIPSCs were normal in both Pv-Cre and Sst-Cre x Tsc1fl/fl knockout mice. These results indicate that removal of TSC1 from all neurons in a local cortical circuit results in hyperexcitability while connections between pyramidal neurons and interneurons expressing PV and SST are preserved in the layer 2/3 visual cortex. Our study suggests that another inhibitory cell type or a combination of multiple subtypes may be accountable for hyperexcitability in TSC.

Tài liệu tham khảo

Hensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005;6:877–88. Katagiri H, Fagiolini M, Hensch TK. Optimization of somatic inhibition at critical period onset in mouse visual cortex. Neuron. 2007;53:805–12. Maffei A, Nataraj K, Nelson SB, Turrigiano GG. Potentiation of cortical inhibition by visual deprivation. Nature. 2006;443:81–4. Yazaki-Sugiyama Y, Kang S, Câteau H, Fukai T, Hensch TK. Bidirectional plasticity in fast-spiking GABA circuits by visual experience. Nature. 2009;462:218–21. Hensch TK. Critical period regulation. Annu Rev Neurosci. 2004;27:549–79. Dorrn AL, Yuan K, Barker AJ, Schreiner CE, Froemke RC. Developmental sensory experience balances cortical excitation and inhibition. Nature. 2010;465:932–6. Rubenstein JLR, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003;2:255–67. Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol. 2007;17:103–11. Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci. 2015;16:551–63. Nelson SB, Valakh V. Excitatory/inhibitory balance and circuit homeostasis in autism Spectrum disorders. Neuron. 2015;87:684–98. Buckley AW, Holmes GL. Epilepsy and autism. Cold Spring Harb Perspect Med. 2016;6:a022749. Staley K. Molecular mechanisms of epilepsy. Nat Neurosci. 2015;18:367–72. Crino PB, Nathanson KL, Henske EP. The Tuberous Sclerosis Complex. NEJM. 2006;355:1345–56. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005;17:596–603. Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 2010;33:67–75. Yoshii A, Constantine-Paton M. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol. 2010;70:304–22. Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, Ramesh V, Silva AJ. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med. 2008;14:843–8. Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci. 2005;8:1727–34. Auerbach BD, Osterweil EK, Bear MF. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature. 2011;480:63-8. Bateup HS, Takasaki KT, Saulnier JL, Denefrio CL, Sabatini BL. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J Neurosci. 2011;31:8862–9. Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL. Excitatory/inhibitory synaptic imbalance leads to hippocampal Hyperexcitability in mouse models of tuberous sclerosis. Neuron. 2013;78:510–22. Huang ZJ, Di Cristo G, Ango F. Development of GABA innervation in the cerebral and cerebellar cortices. Nat Rev Neurosci. 2007;8:673–86. Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C. Interneurons of the neocortical inhibitory system. Nat Rev Neurosci. 2004;5:793–807. Kepecs A, Fishell G. Interneuron cell types are fit to function. Nature. 2014;505:318–26. Marín O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci. 2012;13:107–20. Huang ZJ. Toward a genetic dissection of cortical circuits in the mouse. Neuron. 2014;83:1284–302. Tremblay R, Lee S, Rudy B. GABAergic interneurons in the neocortex: from cellular properties to circuits. Neuron. 2016;91:260–92. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, Ng LL, Palmiter RD, Hawrylycz MJ, Jones AR, Lein ES, Zeng H. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Publ Group. 2009;13:133–40. Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, Kvitsani D, Fu Y, Lu J, Lin Y, Miyoshi G, Shima Y, Fishell G, Nelson SB, Huang ZJ. A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron. 2011;71:995–1013. Taniguchi H, Lu J, Huang ZJ. The spatial and temporal origin of chandelier cells in mouse neocortex. Science. 2013;339:70–4. Chattopadhyaya B. Experience and activity-dependent maturation of Perisomatic GABAergic innervation in primary visual cortex during a postnatal critical period. J Neurosci. 2004;24:9598–611. DeFelipe J, López-Cruz PL, Benavides-Piccione R, Bielza C, Larrañaga P, Anderson S, Burkhalter A, Cauli B, Fairén A, Feldmeyer D, Fishell G, Fitzpatrick D, Freund TF, González-Burgos G, Hestrin S, Hill S, Hof PR, Huang J, Jones EG, Kawaguchi Y, Kisvárday Z, Kubota Y, Lewis DA, Marín O, Markram H, McBain CJ, Meyer HS, Monyer H, Nelson SB, Rockland K, et al. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat Rev Neurosci. 2013;14:202-16. Silberberg G, Markram H. Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells. Neuron. 2007;53:735–46. Atallah BV, Bruns W, Carandini M, Scanziani M. Parvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli. Neuron. 2012;73:159–70. Adesnik H, Bruns W, Taniguchi H, Huang ZJ, Scanziani M. A neural circuit for spatial summation in visual cortex. Nature. 2012;490:226–31. Wilson NR, Runyan CA, Wang FL, Sur M. Division and subtraction by distinct cortical inhibitory networks in vivo. Nature. 2012;488:343–8. Lee S-H, Kwan AC, Zhang S, Phoumthipphavong V, Flannery JG, Masmanidis SC, Taniguchi H, Huang ZJ, Zhang F, Boyden ES, Deisseroth K, Dan Y. Activation of specific interneurons improves V1 feature selectivity and visual perception. Nature. 2012;488:379–83. Ito-Ishida A, Ure K, Chen H, Swann JW, Zoghbi HY. Loss of MeCP2 in Parvalbumin-and somatostatin- expressing neurons in mice leads to distinct Rett syndrome-like phenotypes. Neuron. 2015;88:651–8. Krishnan K, Wang B-S, Lu J, Wang L, Maffei A, Cang J, Huang ZJ. MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. PNAS. 2015;112:E4782–91. Banerjee A, Rikhye RV, Breton-Provencher V, Tang X, Li C, Li K, Runyan CA, Fu Z, Jaenisch R, Sur M. Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome. PNAS. 2016;113:E7287–96. Ogiwara I, Iwasato T, Miyamoto H, Iwata R, Yamagata T, Mazaki E, Yanagawa Y, Tamamaki N, Hensch TK, Itohara S, Yamakawa K. Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome. Hum Mol Genet. 2013;22:4784–804. Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, Jensen FE, Kwiatkowski DJ. A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci. 2007;27:5546–58. Noebels J. Pathway-driven discovery of epilepsy genes. Nat Neurosci. 2015;18:344–50. Soltesz I, Alger BE, Kano M, Lee S-H, Lovinger DM, Ohno-Shosaku T, Watanabe M. Weeding out bad waves: towards selective cannabinoid circuit control in epilepsy. Nat Publ Group. 2015;16:264–77. Goel A, Cantu DA, Guilfoyle J, Chaudhari GR, Newadkar A, Todisco B, Alba D, Kourdougli N, Schmitt LM, Pedapati E, Erickson CA, Portera-Cailliau C. Impaired perceptual learning in a mouse model of fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible. Nat Publ Group. 2018;21:1–14. Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, Kwiatkowski DJ. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling Lead to improved survival and function. J Neurosci. 2008;28:5422–32. Asano E, Chugani DC, Muzik O, Shen C, Juhász C, Janisse J, Ager J, Canady A, Shah JR, Shah AK, Watson C, Chugani HT. Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex. Neurology. 2000;54:1976–84. Asano E, Muzik O, Shah A, Juhász C, Chugani DC, Kagawa K, Benedek K, Sood S, Gotman J, Chugani HT. Quantitative visualization of ictal subdural EEG changes in children with neocortical focal seizures. Clin Neurophysiol. 2004;115:2718–27. Choi YJ, Di Nardo A, Kramvis I, Meikle L, Kwiatkowski DJ, Sahin M, He X. Tuberous sclerosis complex proteins control axon formation. Genes Dev. 2008;22:2485–95. Nie D, Di Nardo A, Han JM, Baharanyi H, Kramvis I, Huynh T, Dabora S, Codeluppi S, Pandolfi PP, Pasquale EB, Sahin M. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci. 2010;13:163–72. Tang G, Gudsnuk K, Kuo S-H, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E, Castagna C, Yamamoto A, Yue Z, Arancio O, Peterson BS, Champagne F, Dwork AJ, Goldman J, Sulzer D. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014;83:1131–43. Mori K, Mori T, Toda Y, Fujii E, Miyazaki M, Harada M, Kagami S. Decreased benzodiazepine receptor and increased GABA level in cortical tubers in tuberous sclerosis complex. Brain Dev. 2012;34:478–86. Talos DM, Sun H, Kosaras B, Joseph A, Folkerth RD, Poduri A, Madsen JR, Black PM, Jensen FE. Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann Neurol. 2012;71:539–51. Petilla Interneuron Nomenclature Group, Ascoli GA, Alonso-Nanclares L, Anderson SA, Barrionuevo G, Benavides-Piccione R, Burkhalter A, Buzsáki G, Cauli B, DeFelipe J, Fairén A, Feldmeyer D, Fishell G, Fregnac Y, Freund TF, Gardner D, Gardner EP, Goldberg JH, Helmstaedter M, Hestrin S, Karube F, Kisvárday ZF, Lambolez B, Lewis DA, Marín O, Markram H, Muñoz A, Packer A, CCH P, Rockland KS, et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat Rev Neurosci. 2008;9:557–68. Le Magueresse C, Monyer H. GABAergic interneurons shape the functional maturation of the cortex. Neuron. 2013;77:388–405. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005;6:312–24. Chao H-T, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu H-C, Heintz N, Ekker M, Rubenstein JLR, Noebels JL, Rosenmund C, Zoghbi HY. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature. 2010;468:263–9. Zhang W, Peterson M, Beyer B, Frankel WN, Zhang Z-W. Loss of MeCP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures. J Neurosci. 2014;34:2754–63. Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy: Dravet syndrome. Adv Neurol. 2005;95:71–102. Tai C, Abe Y, Westenbroek RE, Scheuer T, Catterall WA. Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome. PNAS. 2014;111:E3139–48. Dutton SB, Makinson CD, Papale LA, Shankar A, Balakrishnan B, Nakazawa K, Escayg A. Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility. Neurobiol Dis. 2013;49:211–20. Rubinstein M, Han S, Tai C, Westenbroek RE, Hunker A, Scheuer T, Catterall WA. Dissecting the phenotypes of Dravet syndrome by gene deletion. Brain. 2015;138:2219–33. Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, Tsai L-H, Moore CI. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature. 2009;459:663-7. Mierau SB, Patrizi A, Hensch TK, Fagiolini M. Cell-specific regulation of N-methyl-D-aspartate receptor maturation by Mecp2 in cortical circuits. Biol Psychiatry. 2016;79:746–54. 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. Xue M, Atallah BV, Scanziani M. Equalizing excitation-inhibition ratios across visual cortical neurons. Nature. 2014;511:596–600. Mody I, Pearce RA. Diversity of inhibitory neurotransmission through GABAA receptors. Trends Neurosci. 2004;27:569–75. Fu C, Cawthon B, Clinkscales W, Bruce A, Winzenburger P, Ess KC. GABAergic interneuron development and function is modulated by the Tsc1 gene. Cereb Cortex. 2012;22:2111–9. Vogt D, Cho KKA, Lee AT, Sohal VS, Rubenstein JLR. The Parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles. Cell Rep. 2017;11:1–14.