1. Salva Sadeghi December 1 st, 2009

2.  Definition of Spike-and-Wave Patterns  SWD Observations and Characteristics  Thalamocortical Circuits  Experimental Paper from the Journal of Neuroscience  Activity of Ventral Medial Thalamic Neurons during Absence Seizures and Modulation of Cortical Paroxysms by the Nigrothalamic Pathway (Paz et al., 2007)  References

3.  Spike-and-wave discharge (SWD) refers to a particular EEG pattern  Absence (petit mal) seizure  Clinical: momentary lapse of consciousness due to abnormal electrical activity in the brain  Neuroscience: clear oscillation consisting of generalized and bilaterally synchronous SWDs in the neocortex due to irregularities in the thalamocortical network Typically a frequency of 3 Hz in humans Can be 5-10 Hz in cats and rats

4. (Destexhe, 1992) “Spike” “Wave”

5.  Intracellular recordings indicate that:  Spike – neuronal firing  Wave – hyperpolarization of neurons  Firing of the spike triggers slow K + currents which in turn cause hyperpolarization and result in the wave Slow K + currents Hyper- polarization Spike

6.  Recall: Single cell oscillation in a thalamocortical neuron Ih is active during hyperpolarized state: it repolarizes membrane to IT activation range IT activation results in a wide Ca2+ spike Depolarization occurs and deactivates I h and inactivates IT Membrane is repolarized by slow K + currents and hyperpolarization occurs; cycle continues…. Na + Spike

7.  Outside-in approach: Spike-and-wave seizures disappear following thalamic lesions or by inactivating the thalamus (Pellegrini et al., 1979; Avoli and Gloor, 1981; Vergnes and Marescaux, 1992)  Spindle oscillations, which are generated by thalamic circuits, can be gradually transformed into spike-and-wave discharges and all manipulations that promote or antagonize spindles have the same effect on spike-and-wave seizures (Kostopoulos et al., 1981a, 1981b; McLachlan et al., 1984) (Destexhe, 1998)

8.  An important proportion of thalamic neurons are steadily hyperpolarized and completely silent during cortical seizures with spike-and-wave patterns (Steriade and Contreras, 1995; Lytton et al., 1997; Pinault et al., 1998  Cortical and thalamic cells fire prolonged discharges in phase with the "spike" component, while the "wave" is characterized by a silence in all cell types (Pollen, 1964; Steriade, 1974; Fisher and Prince, 1977b; Avoli et al., 1983; McLachlan et al., 1984; Buzsaki et al., 1988; Inoue et al., 1993; McCormick and Hashemiyoon, 1998; Seidenbecher et al., 1998; Staak and Pape, 2001) Synchronization (Destexhe, 1998)

10. CORTEX 1) Increased cortical excitability leads to SWDs 3) Increased cortical excitability results in runaway excitation/ prolonged firing 5) Strong K + currents result in wave, firing results in spike THALAMUS 2) Strong Inhibitory Feedback (GABA b ) from activated cortex results in IPSPs in thalamic relay cells 4) Cortical feedback continues and IPSPs convert spindle oscillations to 3 Hz SWD providing rebound bursts to continue the cycle

11. Possible influence from the nigrothalamic pathway

12. GABAergic projection Substantia Nigra Strong feedback loop Ventral Medial Thalamic Neurons SWD leads to paroxysms Cortex Hypothesis: GABAergic projections from the substantia nigra pars reticulata (SNR) to thalamocortical neurons of the ventral medial thalamic nucleus provide a potent network for the control of absence seizures by basal ganglia. Pharmalogical blockade of excitatory inputs to nigrothalamic neurons leads to a transient interruption of SWDs by increasing the firing rate of thalamic cells and converting the SWDs into arrhythmic firing patterns.

13.  Purpose 1: Characterize VM thalamic neuron activity during SWD in the GAERS (genetic absence epilepsy rat from Strasbourg).  Purpose 2: Determine impact of a transient blockade of SNR excitation on the firing of VM cells and the result in cortical excitability.

14.  EEG recordings above the orofacial motor cortex with control placed in the muscle on the opposite side of the head  Intracellular recordings to find membrane input resistance  Pharmacology to provide AMPA receptor antagonists  Morphological identification to identify areas

15.  During SWDs, VM firing rate is slow at 7 Hz (accurate for rats which are typically between 5-10 Hz during seizures)  At the end of SWDs, VM firing returns to its natural state of repetitive discharges of APs Repetitive discharge of APs in the VM cells results in end of cortical paroxysms

16.  When an SWD appears in the EEG, the firing of VM cells switches from single spike activity to rhythmic firing, accompanied by membrane potential oscillations temporally correlated with SWDs

17.  During SWD, VM cell experiences subthreshold rhythmic membrane depolarizations during sustained hyperpolarization (caused by IPSPs) Subthreshold depolarizations

18.  Pharmacological blockade: Glutamatergic Antagonist in the SNR Increases rate of firing in VM cells Irregular tonic firing correlated with an interruption of SWDs

19.  Early rhythmic depolarization of VM is attributed to activation of I h due to sustained hyperpolarization  I T is activated from a deinactivated state and can generate Calcium-dependent depolarizations  Nigrothalamic inhibition is indirectly responsible for the deinactivation of I T  Depolarizations act as rebound bursts and can generate APs that propagate the SWD in the cortex

20. GABAergic projection Substantia Nigra Strong feedback loop Ventral Medial Thalamic Neurons SWD leads to paroxysms Cortex Experiment Conclusions (cont.): Disinhibition can terminate seizures in the GAERS model Inhibition of the GABAergic projections results in disinhibition of VM No longer inhibited, the VM neurons fire faster SWDs are terminated and cortical paroxysms end; cortex returns to tonic mode

21. Avoli M., & Gloor P. (1982) Role of the thalamus in generalized penicillin epilepsy: observations on decorticated cats. Exp. Neurol. 77, 386-402. Destexhe, A. (2007) Spike-and-wave oscillations. Scholarpedia, 2(2), 1402. Kostopoulos, G., Gloor, P., Pellegrini, A., & Gotman, J. (1981a) A study of the transition from spindles to spike and wave discharge in feline generalized penicillin epilepsy: microphysiological features. Exp. Neurol. 73, 55-77. McCormick, D.A., & Hashemiyoon, R. (1998) Thalamocortical neurons actively participate in the generation of spike-and-wave seizures in rodents. Soc. Neurosci. Abstracts 24, 129. McLachlan, R.S., Avoli, M., & Gloor, P. (1984) Transition from spindles to generalized spike and wave discharges in the cat: simultaneous single-cell recordings in the cortex and thalamus. Exp. Neurol. 85, 413-425. Paz, J., Chavez, M., Saillet,S., Deniau, J-M., & Charpier, S. (2007). Activity of Ventral Medial Thalamic Neurons during Absence Seizures and Modulation of Cortical Paroxysms by the Nigrothalamic Pathway. Journal of Neuroscience, 27(4), 929-941. Pellegrini, A., Musgrave, J., & Gloor, P. (1979) Role of afferent input of subcortical origin in the genesis of bilaterally synchronous epileptic discharges of feline generalized epilepsy. Exp. Neurol. 64, 155- 173. Pollen, D.A. (1964) Intracellular studies of cortical neurons during thalamic induced wave and spike. Electroencephalogr. Clin. Neurophysiol. 17, 398-404. Vergnes, M., & Marescaux, C. (1992) Cortical and thalamic lesions in rats with genetic absence epilepsy. J. Neural Transmission 35 (Suppl.), 71-83.