Thalamic lesions in a genetic rat model of absence epilepsy: Dissociation between spike-wave discharges and sleep spindles

Meeren, Hanneke K. M.; Veening, Jan G.; Möderscheim, Tanja A.E.; Coenen, A.M.L.; Luijtelaar, Gilles van

doi:10.1016/j.expneurol.2009.01.009

Cited by 85 publications

(85 citation statements)

References 81 publications

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“…These views are supported by earlier studies: Electro-microscopic inspection of the RTN by Liu and Jones (1999) revealed differences in receptive fields between RTN subparts (rostral and the more caudal ventral lateral RTN), and pharmacological and lesion studies revealed that a lesioning/inhibition of the caudal RTN led to an increase in SWD activity (Aker et al, 2006;Meeren et al, 2009), whereas a lesioning/ inhibiting of the oscillator rostral RTN resulted in a decrease of SWD activity (Aker et al, 2006;Berdiev and van Luijtelaar, 2009;Meeren et al, 2009). …”

Section: Interpretation Of Results 1 Andsupporting

confidence: 72%

“…-The intra-RTN communication is involved in the regulation of SWD duration. -The rostral RTN might have a resonator function, which is crucial for SWD maintenance, whereas the caudal RTN might function as a break of this oscillatory activity (see also (Meeren et al, 2009)); -A strong directional drive from cortical focus to Po following the offset of SWD might indicate an SWD re-initiation attempt. This attempt might fail since, in contrast to SWD initiation, no reverberation circuit between cortex and Po is present.…”

Section: Interpretation Of Resultsmentioning

confidence: 99%

“…Regarding the thalamus, next to the VPM also the posterior thalamus (Po) (Kostopoulos, 2001;Lüttjohann and van Luijtelaar, 2012;Polack et al, 2007) was proposed to be crucial while the RTN classically assumed to be relevant for sleep spindles and SWD (Meeren et al, 2005;Steriade, 2003) can no longer be seen as a homogeneous structure but appears to have opposite functions for its caudal and rostral part (Aker et al, 2006;Meeren et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Termination of ongoing spike-wave discharges investigated by cortico–thalamic network analyses

Lüttjohann

Schoffelen

Luijtelaar

2014

Neurobiology of Disease

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a b s t r a c t a r t i c l e i n f oPurpose: While decades of research were devoted to study generation mechanisms of spontaneous spike and wave discharges (SWD), little attention has been paid to network mechanisms associated with the spontaneous termination of SWD. In the current study coupling-dynamics at the onset and termination of SWD were studied in an extended part of the cortico-thalamo-cortical system of freely moving, genetic absence epileptic WAG/Rij rats. Methods: Local-field potential recordings of 16 male WAG/Rij rats, equipped with multiple electrodes targeting layer 4 to 6 of the somatosensory-cortex (ctx4, ctx5, ctx6), rostral and caudal reticular thalamic nucleus (rRTN & cRTN), ventral postero medial (VPM), anterior-(ATN) and posterior (Po) thalamic nucleus, were obtained. Six seconds lasting pre-SWD-N SWD, SWD-N post SWD and control periods were analyzed with timefrequency methods, and between-region interactions were quantified with frequency-resolved Granger Causality (GC) analysis. Results: Most channel pairs showed increases in GC lasting from onset to offset of the SWD. While for most thalamo-thalamic pairs a dominant coupling direction was found during the complete SWD, most corticothalamic pairs only showed a dominant directional drive (always from cortex to thalamus) during the first 500 ms of SWD. Channel pair ctx4-rRTN showed a longer lasting dominant cortical drive, which stopped 1.5 sec prior to SWD offset. This early decrease in directional coupling was followed by an increase in directional coupling from cRTN to rRTN 1 sec prior to SWD offset. For channel pairs ctx5-Po and ctx6-Po the heightened cortex-N thalamus coupling remained until 1.5 sec following SWD offset, while the thalamus-N cortex coupling for these pairs stopped at SWD offset. Conclusion: The high directional coupling from somatosensory cortex to the thalamus at SWD onset is in good agreement with the idea of a cortical epileptic focus that initiates and entrains other brain structures into seizure activity. The decrease of cortex to rRTN coupling as well as the increased coupling from cRTN to rRTN preceding SWD termination demonstrates that SWD termination is a gradual process that involves both cortico-thalamic as well as intrathalamic processes. The rostral RTN seems to be an important resonator for SWD and relevant for maintenance, while the cRTN might inhibit this oscillation. The somatosensory cortex seems to attempt to reinitiate SWD following its offset via its strong coupling to the posterior thalamus.© 2014 Elsevier Inc. All rights reserved. IntroductionAbsence epilepsy (AE) is a neurological disorder, mostly found in young children, which is characterized by frequent, spontaneously starting and spontaneously stopping, lapses of consciousness. The major electrophysiological characteristic of AE are the spontaneously starting and stopping, rhythmic, generalized, bilateral synchronous spike and wave discharges (SWD), which are known to be generated within the cortico-thalamo-cortical system (Depaulis and v...

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Section: Interpretation Of Results 1 Andsupporting

confidence: 72%

Section: Interpretation Of Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Termination of ongoing spike-wave discharges investigated by cortico–thalamic network analyses

Lüttjohann

Schoffelen

Luijtelaar

2014

Neurobiology of Disease

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“…Discussion TRN neurons are thought to be pacemakers for the initiation of thalamocortical oscillations (3,11). Both pharmacological and lesion studies have suggested that rhythmic bursts in the TRN are a key element in generating these oscillations (21,26). However, our results show that tonic firing of TRN neurons in the absence of TRN burst firing is sufficient to generate SWDs, which we believe is a novel observation.…”

Section: Methodsmentioning

confidence: 49%

Rebound burst firing in the reticular thalamus is not essential for pharmacological absence seizures in mice

Lee

Latchoumane

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsic burst and rhythmic burst discharges (RBDs) are elicited by activation of T-type Ca 2+ channels in the thalamic reticular nucleus (TRN). TRN bursts are believed to be critical for generation and maintenance of thalamocortical oscillations, leading to the spikeand-wave discharges (SWDs), which are the hallmarks of absence seizures. We observed that the RBDs were completely abolished, whereas tonic firing was significantly increased, in TRN neurons from mice in which the gene for the T-type Ca 2+ channel, Ca V 3.3, was deleted (Ca V 3.3 −/− ). Contrary to expectations, there was an increased susceptibility to drug-induced SWDs both in Ca V 3.3 −/− mice and in mice in which the Ca V 3.3 gene was silenced predominantly in the TRN. Ca V 3.3 −/− mice also showed enhanced inhibitory synaptic drive onto TC neurons. Finally, a double knockout of both Ca V 3.3 and Ca V 3.2, which showed complete elimination of burst firing and RBDs in TRN neurons, also displayed enhanced drug-induced SWDs and absence seizures. On the other hand, tonic firing in the TRN was increased in these mice, suggesting that increased tonic firing in the TRN may be sufficient for druginduced SWD generation in the absence of burst firing. These results call into question the role of burst firing in TRN neurons in the genesis of SWDs, calling for a rethinking of the mechanism for absence seizure induction.A bsence seizures are generalized, nonconvulsive seizures characterized by the appearance of bilaterally synchronous spike-and-wave discharges (SWDs) on the electroencephalogram (EEG). The frequency of the SWDs is variable among different models and is usually higher (4-12 Hz) in rodents than in humans (3 Hz) (1). SWDs represent synchronized oscillations of the thalamocortical network (2-4), a network that includes neurons of the cerebral cortex, thalamocortical nucleus (TC), and thalamic reticular nucleus (TRN) (5). This thalamocortical circuitry is a key CNS structure for gating the flow of sensory information from the periphery to the cortex (6, 7). Both thalamocortical and corticothalamic connections are mainly glutamatergic (8). The TRN is a shell-like structure that covers most of the rostral, lateral, and ventral parts of the thalamus (5) and is composed exclusively of GABAergic interneurons that provide massive inhibitory input to TC neurons (9). The most distinctive feature of thalamocortical circuitry is its intrinsic ability to generate oscillations via the reciprocal circuits between TC and TRN neurons (10-12).Both TC and TRN neurons are able to generate two distinctive patterns of action potential firing: tonic and burst (13,14). Burst firing is mediated by low-voltage-activated (LVA) T-type Ca 2+ channels (15). There are three subtypes of T-type Ca 2+ channels, called Ca V 3.1, Ca V 3.2, and Ca V 3.3, each with distinctive expression patterns and kinetic properties (16). Within the thalamocortical circuit, Ca V 3.1 channels are predominantly expressed in TC neurons, whereas Ca V 3.2 and Ca V 3.3 channels are expressed only in TR...

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“…S leep spindles are one type of several rhythmic brain waves detected by electroencephalography (EEG) during normal non-rapid eye movement (NREM) sleep. A spindle consists of characteristic waxing-and-waning field potentials grouped into 7-to 14-Hz oscillations that last for 1-3 s and recur once every 5-10 s in the thalamus and the cortex (1)(2)(3). Spindles are also visible under anesthesia, particularly with barbiturates but also with ketamine-xylazine combinations (4,5).…”

Section: T-type Camentioning

confidence: 99%

Sleep spindles are generated in the absence of T-type calcium channel-mediated low-threshold burst firing of thalamocortical neurons

Lee

Song

Lee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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T-type Ca2+ channels in thalamocortical (TC) neurons have long been considered to play a critical role in the genesis of sleep spindles, one of several TC oscillations. A classical model for TC oscillations states that reciprocal interaction between synaptically connected GABAergic thalamic reticular nucleus (TRN) neurons and glutamatergic TC neurons generates oscillations through Ttype channel-mediated low-threshold burst firings of neurons in the two nuclei. These oscillations are then transmitted from TC neurons to cortical neurons, contributing to the network of TC oscillations. Unexpectedly, however, we found that both WT and KO mice for Ca V 3.1, the gene for T-type Ca 2+ channels in TC neurons, exhibit typical waxing-and-waning sleep spindle waves at a similar occurrence and with similar amplitudes and episode durations during non-rapid eye movement sleep. Single-unit recording in parallel with electroencephalography in vivo confirmed a complete lack of burst firing in the mutant TC neurons. Of particular interest, the tonic spike frequency in TC neurons was significantly increased during spindle periods compared with nonspindle periods in both genotypes. In contrast, no significant change in burst firing frequency between spindle and nonspindle periods was noted in the WT mice. Furthermore, spindle-like oscillations were readily generated within intrathalamic circuits composed solely of TRN and TC neurons in vitro in both the KO mutant and WT mice. Our findings call into question the essential role of low-threshold burst firings in TC neurons and suggest that tonic firing is important for the generation and propagation of spindle oscillations in the TC circuit. S leep spindles are one type of several rhythmic brain waves detected by electroencephalography (EEG) during normal non-rapid eye movement (NREM) sleep. A spindle consists of characteristic waxing-and-waning field potentials grouped into 7-to 14-Hz oscillations that last for 1-3 s and recur once every 5-10 s in the thalamus and the cortex (1-3). Spindles are also visible under anesthesia, particularly with barbiturates but also with ketamine-xylazine combinations (4, 5). These oscillations are generated in the thalamus as a result of synaptic interactions between inhibitory [i.e., thalamic reticular nucleus (TRN)] neurons and excitatory thalamocortical (TC) neurons, and are propagated to the cortex. Corticothalamic projections back to the thalamus complete the cortico-thalamo-cortical loop.In vivo data suggest that TRN neurons are spindle pacemakers, because spindles can be generated in deafferented TRN neurons (6) but disappear in TC regions after disconnection from TRN neurons (7). However, in vitro data suggest that an intact TC-TRN network is a necessity, because spindles are abolished after disconnection of TC and TRN neurons (8).Two distinct firing patterns, tonic and burst, are displayed by both TRN and TC neurons. Burst firing is mediated by lowthreshold T-type Ca 2+ channels (9). Of the three subtypes of T-type channels, Ca V 3.1 is expre...

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Thalamic lesions in a genetic rat model of absence epilepsy: Dissociation between spike-wave discharges and sleep spindles

Cited by 85 publications

References 81 publications

Termination of ongoing spike-wave discharges investigated by cortico–thalamic network analyses

Termination of ongoing spike-wave discharges investigated by cortico–thalamic network analyses

Rebound burst firing in the reticular thalamus is not essential for pharmacological absence seizures in mice

Sleep spindles are generated in the absence of T-type calcium channel-mediated low-threshold burst firing of thalamocortical neurons

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