Diminished Presynaptic GABA&lt;sub&gt;B&lt;/sub&gt; Receptor Function in the Neocortex of a Genetic Model of Absence Epilepsy

Inaba, Yugi; D’Antuono, Margherita; Bertazzoni, Giuliano; Biagini, Giuseppe; Avoli, Massimo

doi:10.1159/000197864

Cited by 32 publications

(15 citation statements)

References 41 publications

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“…49 Moreover, the Avoli group reported that higher doses of the GABA B agonist baclophen were required to depress pharmacologically isolated, stimulus-induced inhibitory postsynaptic potentials (IPSPS) generated by WAG/Rij neocortical neurons as compared to those recorded from cells from non-epileptic control (NEC) cells. 50 A similar decreased sensitivity became evident when baclophen was tested on the synchronous network-driven IPSPs generated by neocortical slices treated with 4AP + glutamatergic receptor antagonists. 50 An increase of cortical excitation could also predetermine absence seizures in WAG/Rij rats.…”

Section: Neurophysiological Evidencementioning

confidence: 70%

On the Origin and Suddenness of Absences in Genetic Absence Models

2011

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The origin of spike-wave discharges (SWDs), typical for absences, has been debated for at least half a century. While most classical views adhere to a thalamic oscillatory machinery and an active role of the cortex in modifying normal oscillations into pathological SWDs, recent studies in genetic models such as WAG/Rij and GAERS rats have challenged this proposal. It seems now well established that SWDs originate from the deep layers of the somatosensory cortex, that the activity quickly spreads over the cortex and invades the thalamus. The reticular thalamic nucleus and other thalamic nuclei provide a resonance circuitry for the amplification, spreading and entrainment of the SWDs. Conclusive evidence has been found that the changed functionality of HCN1 channels is a causative factor for the changes in local excitability and age-dependent increase in SWD. Furthermore, upregulation of two subtypes of Na+ channels, reduction of GABAB and mGlu 2/3 receptors might also play a role in the local increased excitability in WAG/Rij rats. Signal analytical studies have also challenged the view that SWDs occur suddenly from a normal background EEG. SWDs are recruited cortical responses and they develop from increasing associations within and between cortical layers and subsequently subcortical regions, triggered by the simultaneous occurrence of theta and delta precursor activity in the cortex and thalamus in case both structures are in a favorable condition, and increased directional coupling between cortex and thalamus. It is hypothesized that the cortex is the driving force throughout the whole SWD and is also responsible for its end.

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Section: Neurophysiological Evidencementioning

confidence: 70%

On the Origin and Suddenness of Absences in Genetic Absence Models

2011

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“…; Inaba et al . ). Alternatively, the persistent membrane depolarization could be caused by an upregulation of voltage‐gated sodium channels as previously reported (Klein et al .…”

Section: Discussionmentioning

confidence: 97%

Integrative properties and transfer function of cortical neurons initiating absence seizures in a rat genetic model

Williams

Altwegg-Boussac

Chávez

et al. 2016

The Journal of Physiology

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Epileptic seizures result from aberrant cellular and/or synaptic properties that can alter the capacity of neurons to integrate and relay information. During absence seizures, spike-and-wave discharges (SWDs) interfere with incoming sensory inputs and preclude conscious experience. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established animal model of absence epilepsy, allows exploration of the cellular basis of this impaired information processing. Here, by combining in vivo electrocorticographic and intracellular recordings from GAERS and control animals, we investigated how the pro-ictogenic properties of seizure-initiating cortical neurons modify their integrative properties and input-output operation during inter-ictal periods and during the spike (S-) and wave (W-) cortical patterns alternating during seizures. In addition to a sustained depolarization and an excessive firing rate in between seizures, ictogenic neurons exhibited a pronounced hyperpolarization-activated depolarization compared to homotypic control neurons. Firing frequency versus injected current relations indicated an increased sensitivity of GAERS cells to weak excitatory inputs, without modifications in the trial-to-trial variability of current-induced firing. During SWDs, the W-component resulted in paradoxical effects in ictogenic neurons, associating an increased membrane input resistance with a reduction in the current-evoked firing responses. Conversely, the collapse of cell membrane resistance during the S-component was accompanied by an elevated current-evoked firing relative to W-sequences, which remained, however, lower compared to inter-ictal periods. These findings show a dynamic modulation of ictogenic neurons' intrinsic properties that may alter inter-seizure cortical function and participate in compromising information processing in cortical networks during absences.

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“…Therefore, neuronal hyperactivity is associated with plastic changes of CB 1 receptors. Interestingly, symptomatic WAG/Rij rats show an increased expression of type‐4 metabotropic glutamate receptors (mGlu4 receptors) in the RTN (Ngomba et al, 2008), an increased expression of mGlu2/3 receptors in the VBTNs and the somatosensory cortex (Ngomba et al, 2005), and a reduced expression and function of GABA B receptors in the neocortex (Merlo et al, 2007; Inaba et al, 2009). In addition, there was a specific loss of alpha3 subunit protein of the GABA A receptors in the RTN (Liu et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

WAG/Rij rats show a reduced expression of CB₁ receptors in thalamic nuclei and respond to the CB₁ receptor agonist, R(+)WIN55,212‐2, with a reduced incidence of spike‐wave discharges

et al. 2010

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SUMMARYPurpose: Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB 1 ) receptors. Methods: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of ''presymptomatic'' 2-month old and ''symptomatic'' 8-month-old WAG/Rij rats relative to agematched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB 1 receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB 1 receptor agonist, R(+)WIN55,212-2 (3-12 mg/kg, s.c.), given alone or combined with the CB 1 receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.).Results: Data showed a reduction of CB 1 receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB 1 receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB 1 receptor agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251. Discussion: These data indicate that the development of absence seizures is associated with plastic modifications of CB 1 receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB 1 receptors are targeted by novel antiabsence drugs.

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Diminished Presynaptic GABA<sub>B</sub> Receptor Function in the Neocortex of a Genetic Model of Absence Epilepsy

Cited by 32 publications

References 41 publications

On the Origin and Suddenness of Absences in Genetic Absence Models

On the Origin and Suddenness of Absences in Genetic Absence Models

Integrative properties and transfer function of cortical neurons initiating absence seizures in a rat genetic model

WAG/Rij rats show a reduced expression of CB₁ receptors in thalamic nuclei and respond to the CB₁ receptor agonist, R(+)WIN55,212‐2, with a reduced incidence of spike‐wave discharges

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Diminished Presynaptic GABA<sub>B</sub> Receptor Function in the Neocortex of a Genetic Model of Absence Epilepsy

Cited by 32 publications

References 41 publications

On the Origin and Suddenness of Absences in Genetic Absence Models

On the Origin and Suddenness of Absences in Genetic Absence Models

Integrative properties and transfer function of cortical neurons initiating absence seizures in a rat genetic model

WAG/Rij rats show a reduced expression of CB1 receptors in thalamic nuclei and respond to the CB1 receptor agonist, R(+)WIN55,212‐2, with a reduced incidence of spike‐wave discharges

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WAG/Rij rats show a reduced expression of CB₁ receptors in thalamic nuclei and respond to the CB₁ receptor agonist, R(+)WIN55,212‐2, with a reduced incidence of spike‐wave discharges