GABAA receptor mediated transmission in the thalamic reticular nucleus of rats with genetic absence epilepsy shows regional differences: Functional implications

Aker, Rezzan; Özyurt, Hazan; Yananlı, Hasan Raci; Çakmak, Yusuf; Özkaynakçi, Aydan E.; Şehirli, Ümit; Saka, Erdi̇nç; Çavdar, Safiye; Onat, Filiz

doi:10.1016/j.brainres.2006.06.118

Cited by 25 publications

(15 citation statements)

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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: 73%

“…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: 73%

Section: Introductionmentioning

confidence: 99%

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

Lüttjohann

Schoffelen

Luijtelaar

2014

Neurobiology of Disease

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“…administration of bicuculline inhibits SWD activity, and in contrast, activation of GABA A receptors by muscimol causes a dose-dependent increase in the number of SWD complexes in the WAG/ Rij model (26). A connection between posterior hypothalamic area and thalamus was reported previously (27). Based on the findings about the decrease in SWD activity in response to bicuculline injections, we can assume the involvement of the posterior hypothalamic regions in the generation of SWDs or an interaction between the hypothalamus and cortico-reticular system (or cortico-thalamic system) that generate SWDs.…”

Section: Discussionsupporting

confidence: 54%

Extracellular Hypothalamic γ-Aminobutyric Acid (GABA) and L-Glutamic Acid Concentrations in Response to Bicuculline in a Genetic Absence Epilepsy Rat Model

et al. 2008

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Abstract. The posterior part of the hypothalamus plays a vital role in the homeostatic processes of the internal environment, including blood pressure and heart rate regulation, by means of γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission. In this study we measured the extracellular levels of GABA and L-glutamic acid in the dorsomedial hypothalamic nucleus (DMH) and posterior hypothalamus (PH), following intracerebroventricular (i.c.v.) administration of bicuculline, a GABA A -receptor antagonist, in genetic absence epileptic rats from Strasbourg (GAERS), where heart rate, blood pressure, and EEG recordings were also collected simultaneously. The i.c.v. injection of bicuculline (0.3 nmol) produced no response in nonepileptic Wistar rats but caused an increase in mean arterial pressure in GAERS (P<0.01). Microdialysis experiments showed that L-glutamic acid increased in the DMH in GAERS after bicuculline administration (P<0.01). Additionally, extracellular GABA concentration decreased in the PH (P<0.05). Bicuculline suppressed the spike-and-wave discharges, the characteristic sign of absence seizures. All these results suggest that the bicuculline-induced blood pressure response is accompanied by changes in L-glutamic acid levels in the DMH and GABA levels in the PH, indicating a bicuculline hypersensitivity in the DMH and PH of GAERS that may make the GAERS display an altered mode of central cardiovascular regulation. These results suggest that the circuits affected in GAERS are not only restricted to the regions responsible for seizure generation but also present in the hypothalamus.

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“…In addition, it is generally accepted that the relay nuclei in the ventrobasal part of the thalamus as well as the reticular thalamic nucleus (RTN), the main source of GABA-ergic inhibition in the rat's thalamus, play major roles in the generation of SWDs. A focal origin in the deep layers of the somatosensory cortex has been demonstrated in WAG/Rij, GAERS, Long Evans and PTZ seizure models (Meeren et al, 2002; Polack et al, 2007; Chen et al, 2011), and lesions and network studies propose opposite roles for the rostral and caudal part of the RTN (Aker et al, 2006; Lüttjohann et al, 2014), and a prominent role of the ventrolateral thalamus and posterior nucleus of the thalamus (Crunelli and Leresche, 2002; Pinault and O'Brien, 2005; Meeren et al, 2009; Lüttjohann and van Luijtelaar, 2012). Studies in GAERS have revealed a strong modulatory role of the basal ganglia on the occurrence of SWDs which in turn could affect cortical neuron excitability and, consequently, the generation of cortical epileptic discharges (Paz et al, 2007).…”

Section: Network Involved In Absence Epilepsymentioning

confidence: 99%

“…This reverberating circuit is modulated and driven by reciprocal intrathalamic connections between the Re and rostral RTN (8). In typical absence epilepsy, pharmacological, lesion, and signal analytical studies indicate opposite roles for the rostral and caudal part of the RTN (Aker et al, 2002, 2006; Meeren et al, 2009; Lüttjohann and van Luijtelaar, 2012). To illustrate, administration of bicuculline into the caudal RTN produced increases in the duration of SWDs (9), whereas injections into the rostral RTN produced significant decreases (10).…”

Section: Highlightsmentioning

confidence: 99%

Animal models of absence epilepsies: What do they model and do sex and sex hormones matter?

Luijtelaar

Onat

Gallagher

2014

Neurobiology of Disease

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While epidemiological data suggest a female prevalence in human childhood- and adolescence-onset typical absence epilepsy syndromes, the sex difference is less clear in adult-onset syndromes. In addition, although there are more females than males diagnosed with typical absence epilepsy syndromes, there is a paucity of studies on sex differences in seizure frequency and semiology in patients diagnosed with any absence epilepsy syndrome. Moreover, it is unknown if there are sex differences in the prevalence or expression of atypical absence epilepsy syndromes. Surprisingly, most studies of animal models of absence epilepsy either did not investigate sex differences, or failed to find sex-dependent effects. However, various rodent models for atypical syndromes such as the AY9944 model (prepubertal females show a higher incidence than prepubertal males), BN model also with a higher prevalence in males and the Gabra1 deletion mouse in the C57BL/6J strain offer unique possibilities for the investigation of the mechanisms involved in sex differences. Although the mechanistic bases for the sex differences in humans or these three models are not yet known, studies of the effects of sex hormones on seizures have offered some possibilities. The sex hormones progesterone, estradiol and testosterone exert diametrically opposite effects in genetic absence epilepsy and pharmacologically-evoked convulsive types of epilepsy models. In addition, acute pharmacological effects of progesterone on absence seizures during proestrus are opposite to those seen during pregnancy. 17β-Estradiol has anti-absence seizure effects, but it is only active in atypical absence models. It is speculated that the pro-absence action of progesterone, and perhaps also the delayed pro-absence action of testosterone, are mediated through the neurosteroid allopregnanolone and its structural and functional homolog, androstanediol. These two steroids increase extrasynaptic thalamic tonic GABAergic inhibition by selectively targeting neurosteroid-selective subunits of GABAA receptors (GABAARs). Neurosteroids also modulate the expression of GABAAR containing the γ2, α4, and δ subunits. It is hypothesized that differences in subunit expression during pregnancy and ovarian cycle contribute to the opposite effects of progesterone in these two hormonal states.

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GABAA receptor mediated transmission in the thalamic reticular nucleus of rats with genetic absence epilepsy shows regional differences: Functional implications

Cited by 25 publications

References 47 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

Extracellular Hypothalamic γ-Aminobutyric Acid (GABA) and L-Glutamic Acid Concentrations in Response to Bicuculline in a Genetic Absence Epilepsy Rat Model

Animal models of absence epilepsies: What do they model and do sex and sex hormones matter?

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