Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1

Yanling Wang, Joel S F Greenwood, Maria Elisa Calcagnotto, Heidi E. Kirsch, Nicholas Barbaro, Scott C. Baraban

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Objective: To identify brain regions, cell types, or both that generate abnormal electrical discharge in tuberous sclerosis complex (TSC). Here we examined excitatory and inhibitory synaptic currents in human tissue samples obtained from a TSC patient with no discernible cortical tubers and acute neocortical brain slices from a mouse featuring synapsin-driven conditional deletion of a TSC1 gene. These studies were designed to assess whether TSC gene inactivation alters excitability. Methods: We used visualized patch-clamp (human and mouse) and extracellular field (mouse) recordings. Additional mice were processed for immunohistochemistry or Western blot analysis. Results: Detailed anatomic studies in brain tissue sections from synapsin-TSC1 conditional knock-out mice failed to uncover gross anatomic defects, loss of lamination, or frank tuber formation. However, regions of abnormal and potentially activated neocortex were shown using antibodies to nonphosphorylated neurofilaments (SMI-311) and immediate early genes (c-Fos). Extracellular recordings from neocortical slices, examining synaptic activity in these regions, demonstrated clear differences in excitability between conditional knock-out and age-matched control mice. Whole-cell patch-clamp recordings demonstrated excitatory synaptic currents with strikingly long duration and epileptiform discharge patterns, similar to waveforms observed in our human tissue samples. These events were 1-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor mediated and were most prominent in neocortex. Normal-appearing inhibitory postsynaptic currents (human) and intrinsic neuronal firing patterns (mouse) were also recorded. Interpretation: This combination of human and mouse tissue studies suggests, for the first time, that synaptic excitation is altered in a direction that favors seizure generation in TSC brain tissue regardless of cortical tubers.

Original languageEnglish (US)
Pages (from-to)139-152
Number of pages14
JournalAnnals of Neurology
Volume61
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

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Tuberous Sclerosis
Synapsins
Neocortex
Brain
Inhibitory Postsynaptic Potentials
Immediate-Early Genes
AMPA Receptors
Intermediate Filaments
Gene Silencing
Knockout Mice
Seizures
Western Blotting
Immunohistochemistry
Antibodies
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Wang, Y., Greenwood, J. S. F., Calcagnotto, M. E., Kirsch, H. E., Barbaro, N., & Baraban, S. C. (2007). Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. Annals of Neurology, 61(2), 139-152. https://doi.org/10.1002/ana.21058

Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. / Wang, Yanling; Greenwood, Joel S F; Calcagnotto, Maria Elisa; Kirsch, Heidi E.; Barbaro, Nicholas; Baraban, Scott C.

In: Annals of Neurology, Vol. 61, No. 2, 02.2007, p. 139-152.

Research output: Contribution to journalArticle

Wang, Y, Greenwood, JSF, Calcagnotto, ME, Kirsch, HE, Barbaro, N & Baraban, SC 2007, 'Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1', Annals of Neurology, vol. 61, no. 2, pp. 139-152. https://doi.org/10.1002/ana.21058
Wang, Yanling ; Greenwood, Joel S F ; Calcagnotto, Maria Elisa ; Kirsch, Heidi E. ; Barbaro, Nicholas ; Baraban, Scott C. / Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. In: Annals of Neurology. 2007 ; Vol. 61, No. 2. pp. 139-152.
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