Thalamocortical Mechanisms - Absence Epilepsy

Epilepsy is one of the most serious and widespread neurological diseases, that affects about 1% of the population with significant morbidity and mortality. It is still often associated with social segregation and its presence from a young age to senility represents a substantial economical burden to

society. Notwithstanding these health and financial implications, and because of the unwelcome lack of interest by the media, publicly-funded financial support for research into epilepsy as well as interest by the next generation of neuroscientists into this multi-faceted disorder has drastically decreased in the last 10 years. Moreover, all the large pharmaceutical companies have withdrawn from active research into epilepsy treatment, because of the perceived smaller market compared to neurodegenerative disorders. Clinical and basic research into the mechanism(s) of this debilitating disease, therefore, has now shrunk to its lowest, leading to a highly uncertain future, particularly for patient cohorts suffering from those forms of epilepsy with a complex genotype.

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Absence Epilepsy

A typical absence episode is a non-convulsive epileptic seizure that is characterized by a sudden and relatively brief impairment of con- sciousness, occurring con- comitantly with a genera- lized and bilaterally syn- chronous ‘(poly)spike and wave discharge’ (SWD) paroxysm at 2.5-4 Hz in the EEG (Fig. 1). Typical absence seizures are part of the complex clinical and EEG presentation of a number of idiopathic generalized epi- lepsies (IGEs), though in childhood absence epilepsy these seizures very often represent the only neurolo- gical symptom and are not accompanied by metabolic, neuropathological or other neurolo- gical deficits. Typical absence seizures are genetically determined, and there is strong consensus in describing this type of epilepsy as a familial disease with a complex genotype. Indeed, increasing evidence suggests that absence seizures may represent a complex channelopathy of multi-factorial genetic background.

This view is supported by many association studies and by the presence of genetic abnormalities and/or mutations in various neurotransmitter- and voltage-gated channels in different IGE cohorts. Among these, GABA-A rece- ptors and low-voltage activated T-type Ca²⁺ channels are undoub- tedly those for which the most solid evidence is available, though due to the diverse and complex clinical and EEG presentation of the majority of the investigated cohorts, it is still difficult to unequivocally link these genetic abnormalities with a well-defined epileptic phenotype except in the case of a few rare families. Data from some old invasive studies and recent PET, fMRI and high density EEG investigations have also brought about a general consensus on the key involvement of reciprocally con-nected thalamic and cortical territories, i.e. what are generally referred to as thalamo-cortico-thalamic networks (Fig. 2), to the expression of human absence seizures. However, the notion that typical absence seizures are truly ‘generalized’ from the very start of the EEG manifestation of a seizure has been recently challenged by the observation that seizure onset is associated with paro- xysmal activation of discrete, often unila- teral, frontal cortical regions before sprea- ding to the entire cortical mantel. This scenario is also evident in experimental models of absence epilepsy, thought in this case the electrographic component of the seizure appear first over the somatosensory cortex. Indeed, the anti-absence drug Ethosuximide has a much stronger effect when administered in this cortical site than in the thalamus (Fig. 3).

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OUR RESEARCH

Our work has significantly contributed to an increased understanding of the pathophysiological mechanisms of absence epilepsy. In particular, our major findings in this field include:

Ø identification of an altered GAT-1 activity leading to an enhanced tonic GABA-A current of thalamocortical neurons as a requisite for the expression of typical absence seizures, and of the its (Figs. 4 & 5)

(see publications 1 and 5, below)

Ø elucidation of the mechanism and site of action of ethosuximide, one of the most widely used drugs for treatment of absence epilepsy (Fig. 3)

(see publications 8, 9, 12, 13 and 15, below)

Ø characterization of the paroxysmal activity expressed by the main neuronal cell types in thalamus and cortex during spike and wave discharges of typical absence seizures (Fig. 6)

(see publications 4, 10, 11, 12, 14 and 16, below)

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We are continuing to investigate the cellu- lar and network basis that underlie the generation of absen- ce seizures, with the aim of improving our knowledge and provi- de novel avenues of therapeutic interven- tions. We are thus conducting in vitro and in vivo experi- ments in different models of this neuro- logical disease, and in particular, we are i) studying the firing dynamics of large cortical and thalamic neuronal ensembles during absence seizu- res in vivo, ii) testing novel selective anta- gonists of different neuronal membrane channels involved in absence epilepsy, and iii) investigating the role of thalamic and cortical astrocy- tes in this type of epilepsy.

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Details of our discoveries in this field can be found in the following publications:

1. Cope, D.W., Fyson, S.J., Errington, A.C., Di Giovanni, G., Lörincz, M., Orbán, G., Gould, T.M., Carter, D.A. and Crunelli V. (2009). Enhanced tonic GABAergic inhibition is required for typical absence seizures. Nature Medicine, 15, 1392-1398.

2. Toth, T.I., Bessaih, T., Leresche, N. and Crunelli, V. (2007). Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures. Eur. J. Neurosci., 26, 1832-1844.

3. Crunelli, V., Emri, Zs. and Leresche, N. (2006). Unravelling the brain targets of g-hydroxybutyric acid. Curr. Opin. Pharmacol., 6, 44-52.

4. Bessaih, T., Bourgeais, L., Badiu, C.I., Carter, D.A., Toth, T.I., Ruano, D., Lambolez, B., Crunelli, V. and Leresche, N. (2006). Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures. J. Neurophysiol., 96, 3074-3081.

5. Cope, D.W., Hughes, S.W and Crunelli V. (2005) GABA_A receptor-mediated tonic inhibition in thalamic neurons. J. Neurosci., 25, 11553-11563.

6. Holter, J., Carter, D.A., Leresche, N., Crunelli, V. and Vincent, P. (2005) A TASK3 channel (KCNK9) mutation in a genetic model of absence epilepsy. J. Mol. Neurosci., 25, 37-52.

7. Holter, J., Davies, J, Leresche, N., Crunelli, V. and Carter D.A. (2005) Identification of two further splice variants of GABABR1 characterizes the conserved micro-exon 4 as a hot spot for regulated splicing in the brain. J. Mol. Neurosci., 26, 99-108.

8. Manning, J-P., A., Richards, D.A., Leresche, N., Crunelli, V. and Bowery, N.G. (2004) Cortical-area specific block of genetically determined absence seizures by ethosuximide. Neuroscience, 123, 5-9.

9. Richards, D.A., Manning J-P. A., Barnes, D., Rombola, L., Bowery, N.G., Caccia, S., Leresche, N. and Crunelli, V.(2003) Targeting thalamic nuclei is not sufficient for the full anti-absence action of ethosuximide in a model of absence epilepsy. Epil. Res., 54, 97-107.

10. Gervasi, N., Monnier, Z., Vincent, P., Paupardin-Tritsch, D., Hughes, S.W., Crunelli, V.and Leresche, N. (2003) Pathway specific action of GHB in sensory thalamus and its relevance to absence seizures. J. Neurosci., 23, 11469-11478.

11. Slaght, S.J., Leresche, N., Deniau, J-M., Crunelli, V. and Charpier, S. (2002). Activity of thalamic reticular neurons during spontaneous genetically determined spike and wave discharges. J. Neurosci., 22, 2323-2334.

12. Crunelli, V. and Leresche, N. (2002). Childhood absence epilepsy: genes, channels, neurons and networks. Nature Review Neuroscience, 3, 371-382.

13. Crunelli, V. and Leresche, N. (2002). Block of thalamic T-type Ca²⁺ channels by ethosuximide is not the whole story. Epil. Curr., 2, 53-56.

14. Charpier, S., Leresche, N., Deniau, J-M., Mahon, S., Hughes, S.W. and Crunelli, V. (1999) On the putative contribution of GABA_B receptors to the electrical events occuring during spontaneous spike and wave discharges. Neuropharmacol., 38, 1699-1706.

15. Leresche, N., Parri. H.R., Erdemli, G., Guyon, A., Turner, J.P., Williams, S.R., Asprodini, E. and Crunelli, V. (1998). On the action of the anti-absence drug ethosuximide in the thalamus. J. Neurosci., 18, 4842-4853.

16. Pinault, D., Leresche, N., Charpier, S., Deniau, J-M., Marescaux, C., Vergnes, M. and Crunelli, V. (1998). Intracellular recordings in thalamic neurones during spontaneous spike and wave discharges in absence epilepsy. J. Physiol., 509, 449-456.

17. Emri, Zs., Turner, J.P. and Crunelli, V. (1996). Tonic activation of presynaptic GABA_B receptors on thalamic sensory afferents. Neuroscience, 72, 689-698.

18. Emri, Zs., Antal, K. and Crunelli, V. (1996). Gamma-hydroxybutyric acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABA_B receptors. Neurosci. Lett., 216, 121-124.

19. Williams, S.R., Turner, J.P. and Crunelli, V. (1995). Gamma-hydroxybutyrate promotes oscillatory activity of thalamocortical neurons by a tonic GABA_B receptor-mediated hyperpolarization. Neuroscience, 66, 133-141.

20. Soltesz, I. and Crunelli, V. (1992). GABAA and pre- and post-synaptic GABAB receptor-mediated responses in the lateral geniculate nucleus. Prog. Brain Res. 90, 151-169.

21. Crunelli, V. and Leresche, N. (1991). A role for GABA_B receptors in excitation and inhibition of thalamocortical cells. Trends Neuroscience, 14, 16-21.