Salva SadeghiDecember 1st, 2009

OUTLINE 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

Spike-and-wave discharge (SWD) refers to a particular EEG pattern

Absence (petit mal) seizureClinical: 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

(Destexhe, 1992) “Spike”

“Wave”

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

Recall: Single cell oscillation in a thalamocortical neuron

Na+ Spike

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)

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)

(Destexhe, 1998)

CORTEX1) Increased cortical excitability leads to SWDs3) Increased cortical excitability results in runaway excitation/ prolonged firing5) Strong K+ currents result in wave, firing results in spike

THALAMUS2) Strong Inhibitory

Feedback (GABAb) 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

Possible influence from the nigrothalamic pathway

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.

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.

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

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

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

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

Subthreshold depolarizations

Pharmacological blockade:

Early rhythmic depolarization of VM is attributed to activation of Ih due to sustained hyperpolarization

IT is activated from a deinactivated state and can generate Calcium-dependent depolarizations

Nigrothalamic inhibition is indirectly responsible for the deinactivation of IT

Depolarizations act as rebound bursts and can generate APs that propagate the SWD in the cortex

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

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.