Synaptic Hyperexcitability of Cytomegalic Pyramidal Neurons Contributes to Epileptogenesis in Tuberous Sclerosis Complex

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2022 Jul 20

PMID 35858542

Authors

Xiaoping Wu

Alexander A Sosunov

Wudu Lado

Jia Jie Teoh

Ahrom Ham

Hongyu Li

Osama Al-Dalahmah

Brian J A Gill

Ottavio Arancio

Catherine A Schevon

Wayne N Frankel

Guy M McKhann 2nd

David Sulzer

James E Goldman

Guomei Tang

Affiliations

Soon will be listed here.

Abstract

Tuberous sclerosis complex (TSC) is a developmental disorder associated with epilepsy, autism, and cognitive impairment. Despite inactivating mutations in the TSC1 or TSC2 genes and hyperactive mechanistic target of rapamycin (mTOR) signaling, the mechanisms underlying TSC-associated neurological symptoms remain incompletely understood. Here we generate a Tsc1 conditional knockout (CKO) mouse model in which Tsc1 inactivation in late embryonic radial glia causes social and cognitive impairment and spontaneous seizures. Tsc1 depletion occurs in a subset of layer 2/3 cortical pyramidal neurons, leading to development of cytomegalic pyramidal neurons (CPNs) that mimic dysplastic neurons in human TSC, featuring abnormal dendritic and axonal overgrowth, enhanced glutamatergic synaptic transmission, and increased susceptibility to seizure-like activities. We provide evidence that enhanced synaptic excitation in CPNs contributes to cortical hyperexcitability and epileptogenesis. In contrast, astrocytic regulation of synapse formation and synaptic transmission remains unchanged after late embryonic radial glial Tsc1 inactivation, and astrogliosis evolves secondary to seizures.

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References

Lozovaya N, Gataullina S, Tsintsadze T, Tsintsadze V, Pallesi-Pocachard E, Minlebaev M . Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nat Commun. 2014; 5:4563. PMC: 4143949. DOI: 10.1038/ncomms5563. View

Lin T, Hsieh L, Kimura T, Malone T, Bordey A . Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration. Proc Natl Acad Sci U S A. 2016; 113(40):11330-11335. PMC: 5056085. DOI: 10.1073/pnas.1605740113. View

Anderl S, Freeland M, Kwiatkowski D, Goto J . Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex. Hum Mol Genet. 2011; 20(23):4597-604. PMC: 3209830. DOI: 10.1093/hmg/ddr393. View

Normand E, Crandall S, Thorn C, Murphy E, Voelcker B, Browning C . Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior. Neuron. 2013; 78(5):895-909. PMC: 4529124. DOI: 10.1016/j.neuron.2013.03.030. View

Sosunov A, McGovern R, Mikell C, Wu X, Coughlin D, Crino P . Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities. Acta Neuropathol Commun. 2015; 3:17. PMC: 4383198. DOI: 10.1186/s40478-015-0191-5. View

Errico F, Mothet J, Usiello A . D-Aspartate: An endogenous NMDA receptor agonist enriched in the developing brain with potential involvement in schizophrenia. J Pharm Biomed Anal. 2015; 116:7-17. DOI: 10.1016/j.jpba.2015.03.024. View

Hotka M, Kubista H . The paroxysmal depolarization shift in epilepsy research. Int J Biochem Cell Biol. 2018; 107:77-81. PMC: 7116775. DOI: 10.1016/j.biocel.2018.12.006. View

Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M . 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(21):5422-32. PMC: 2633923. DOI: 10.1523/JNEUROSCI.0955-08.2008. View

Lim J, Gopalappa R, Kim S, Ramakrishna S, Lee M, Kim W . Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia. Am J Hum Genet. 2017; 100(3):454-472. PMC: 5339289. DOI: 10.1016/j.ajhg.2017.01.030. View

10.

Sutula T, Cascino G, Cavazos J, Parada I, Ramirez L . Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol. 1989; 26(3):321-30. DOI: 10.1002/ana.410260303. View

11.

Tang G, Gudsnuk K, Kuo S, Cotrina M, Rosoklija G, Sosunov A . Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014; 83(5):1131-43. PMC: 4159743. DOI: 10.1016/j.neuron.2014.07.040. View

12.

Proietti Onori M, Koene L, Schafer C, Nellist M, de Brito Van Velze M, Gao Z . RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity. PLoS Biol. 2021; 19(5):e3001279. PMC: 8186814. DOI: 10.1371/journal.pbio.3001279. View

13.

Meikle L, McMullen J, Sherwood M, Lader A, Walker V, Chan J . A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes. Hum Mol Genet. 2004; 14(3):429-35. DOI: 10.1093/hmg/ddi039. View

14.

Cox R, de Anda F, Mangoubi T, Yoshii A . Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in -Suppressed Brain. Front Mol Neurosci. 2018; 11:409. PMC: 6237075. DOI: 10.3389/fnmol.2018.00409. View

15.

Polleux F, Dehay C, Kennedy H . The timetable of laminar neurogenesis contributes to the specification of cortical areas in mouse isocortex. J Comp Neurol. 1997; 385(1):95-116. View

16.

Crino P . Evolving neurobiology of tuberous sclerosis complex. Acta Neuropathol. 2013; 125(3):317-32. DOI: 10.1007/s00401-013-1085-x. View

17.

Cepeda C, Andre V, Yamazaki I, Hauptman J, Chen J, Vinters H . Comparative study of cellular and synaptic abnormalities in brain tissue samples from pediatric tuberous sclerosis complex and cortical dysplasia type II. Epilepsia. 2010; 51 Suppl 3:160-5. PMC: 2909023. DOI: 10.1111/j.1528-1167.2010.02633.x. View

18.

Cela E, McFarlan A, Chung A, Wang T, Chierzi S, Murai K . An Optogenetic Kindling Model of Neocortical Epilepsy. Sci Rep. 2019; 9(1):5236. PMC: 6437216. DOI: 10.1038/s41598-019-41533-2. View

19.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

20.

Jansen L, Uhlmann E, Crino P, Gutmann D, Wong M . Epileptogenesis and reduced inward rectifier potassium current in tuberous sclerosis complex-1-deficient astrocytes. Epilepsia. 2006; 46(12):1871-80. DOI: 10.1111/j.1528-1167.2005.00289.x. View