Cellular and molecular mechanisms of new onset seizure generation

  • Gabriele LosiEmail author
  • Marta Gomez-Gonzalo
  • Micaela Zonta
  • Angela Chiavegato
  • Giorgio CarmignotoEmail author
Short Communication


New onset epilepsy and seizures are common neurological disorders in aged people, second only to stroke and dementia. They are frequently related to other pathological conditions including stroke, trauma, tumors and neurological diseases whereas in about one-third of cases the origin is unknown. Besides the origin, the cellular and molecular events that suddenly trigger seizures are poorly defined. Using an acute model of seizure generation that better resembles new onset seizures, we studied GABAergic interneurons and astrocytes during seizure generation. We found that seizures are preceded by a GABAergic rhythmic hyperactivity that synchronizes pyramidal neurons by inducing a rebound spiking that favors seizures’ onset. Furthermore, the intense activity in GABAergic interneurons evokes Ca2+ elevations in astrocytes that, by releasing glutamate, further excite neuronal network. Elucidating the cellular and molecular events that generate seizures may reveal new targets for treatment of new onset seizures and epilepsy.


Seizures Epilepsy GABA Interneurons Astrocytes Cytokines 



This work was supported by the National Research Council of Italy (CNR), Research Project “Aging: molecular and technological innovations for improving the health of the elderly population” (Prot. MIUR 2867 25.11.2011).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding authors declare that there is no conflict of interest.

Statement of human and animal rights

All procedures performed in the original studies described in this contribution were in accordance with the ethical standards of the institutional research committee (Ethical approval by the Ethical Committee of both the University of Padova and the Italian Ministry of Education, University and Research).

Informed consent

No human participant was included in the studies described in this contribution.


  1. 1.
    Beghi E, Giussani G (2018) Aging and the epidemiology of epilepsy. Neuroepidemiology. 51:216–223CrossRefGoogle Scholar
  2. 2.
    Liu Shasha, Weihua Yu, Lü Yang (2016) The causes of new-onset epilepsy and seizures in the elderly. Neuropsychiatr Dis Treat. 12:1425–1434CrossRefGoogle Scholar
  3. 3.
    Losi G, Cammarota M, Chiavegato A et al (2010) A new experimental model of focal seizures in the entorhinal cortex. Epilepsia 51:1493–1502CrossRefGoogle Scholar
  4. 4.
    Gómez-Gonzalo M, Losi G, Chiavegato A et al (2010) An excitatory loop with astrocytes contributes to drive neurons to seizure threshold. PLoS Biol 8:e1000352CrossRefGoogle Scholar
  5. 5.
    Losi G, Marcon I, Mariotti L et al (2015) A brain slice experimental model to study the generation and the propagation of focally-induced epileptiform activity. J Neurosci Methods 260:125–131CrossRefGoogle Scholar
  6. 6.
    Librizzi L, Losi G, Marcon I et al (2017) Interneuronal network activity at the onset of seizure-like events in entorhinal cortex slices. J Neurosci 37:10398–10407CrossRefGoogle Scholar
  7. 7.
    de Curtis M, Avoli M (2016) GABAergic networks jump-start focal seizures. Epilepsia 57:679–687CrossRefGoogle Scholar
  8. 8.
    Cammarota M, Losi G, Chiavegato A et al (2013) Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy. J Physiol 591:807–822CrossRefGoogle Scholar
  9. 9.
    Sessolo M, Marcon I, Bovetti S et al (2015) Parvalbumin-positive inhibitory interneurons oppose propagation but favor generation of focal epileptiform activity. J Neurosci 35:9544–9557CrossRefGoogle Scholar
  10. 10.
    Noam Y, Bernard C, Baram TZ (2011) Towards an integrated view of HCN channel role in epilepsy. Curr Opin Neurobiol 21:873–879. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Pekny M, Pekna M, Messing A et al (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345CrossRefGoogle Scholar
  12. 12.
    Fellin T, Pascual O, Gobbo S et al (2004) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43:729–743CrossRefGoogle Scholar
  13. 13.
    Mariotti L, Losi G, Sessolo M et al (2016) The inhibitory neurotransmitter GABA evokes long-lasting Ca2+ oscillations in cortical astrocytes. Glia 64:363–373CrossRefGoogle Scholar
  14. 14.
    Mariotti L, Losi G, Lia A et al (2018) Interneuron-specific signaling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes. Nat Commun 9:82CrossRefGoogle Scholar
  15. 15.
    Vezzani A, French J, Bartfai T et al (2011) The role of inflammation in epilepsy. Nat Rev Neurol. 7:31–40CrossRefGoogle Scholar
  16. 16.
    Chiavegato A, Zurolo E, Losi G et al (2014) The inflammatory molecules IL-1β and HMGB1 can rapidly enhance focal seizure generation in a brain slice model of temporal lobe epilepsy. Front Cell Neurosci. 8:155CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Neuroscience InstituteNational Research Council (CNR)PaduaItaly
  2. 2.Department of Biomedical ScienceUniversity of PaduaPaduaItaly

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