62 research outputs found

    Enhanced tonic GABAA inhibition in typical absence epilepsy

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    The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent ‘tonic’ inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT–1 in the genetic models tested, and GAT–1 is critical in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.peer-reviewe

    The role of the medial geniculate body of the thalamus in the pathophysiology of tinnitus and implications for treatment

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    Tinnitus is an auditory sensation in the absence of actual external stimulation. Different clinical interventions are used in tinnitus treatment, but only few patients respond to available options. The lack of successful tinnitus treatment is partly due to the limited knowledge about the mechanisms underlying tinnitus. Recently, the auditory part of the thalamus has gained attention as a central structure in the neuropathophysiology of tinnitus. Increased thalamic spontaneous firing rate, bursting activity and oscillations, alongside an increase of GABAergic tonic inhibition have been shown in the auditory thalamus in animal models of tinnitus. In addition, clinical neuroimaging studies have shown structural and functional thalamic changes with tinnitus. This review provides a systematic overview and discussion of these observations that support a central role of the auditory thalamus in tinnitus. Based on this approach, a neuromodulative treatment option for tinnitus is proposed

    Muscarinic regulation of dendritic and axonal outputs of rat thalamic interneurons: A new cellular mechanism for uncoupling distal dendrites

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    Inhibition is crucial for sharpening the sensory information relayed through the thalamus. To understand how the interneuron-mediated inhibition in the thalamus is regulated, we studied the muscarinic effects on interneurons in the lateral posterior nucleus and lateral geniculate nucleus of the thalamus. Here, we report that activation of muscarinic receptors switched the firing pattern in thalamic interneurons from bursting to tonic. Although neuromodulators switch the firing mode in several other types of neurons by altering their membrane potential, we found that activation of muscarinic subtype 2 receptors switched the fire mode in thalamic interneurons by selectively decreasing their input resistance. This is attributable to the muscarinic enhancement of a hyperpolarizing potassium conductance and two depolarizing cation conductances. The decrease in input resistance appeared to electrotonically uncouple the distal dendrites of thalamic interneurons, which effectively changed the inhibition pattern in thalamocortical cells. These results suggest a novel cellular mechanism for the cholinergic transformation of long-range, slow dendrite- and axon-originated inhibition into short-range, fast dendrite-originated inhibition in the thalamus observed in vivo. It is concluded that the electrotonic properties of the dendritic compartments of thalamic interneurons can be dynamically regulated by muscarinic activity

    CELLULAR AND CIRCUIT PROPERTIES OF SLOW OSCILLATIONS IN THE THALAMIC RETICULAR NUCLEUS

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    During sleep, neurons in the thalamic reticular nucleus (TRN) generate distinct types of oscillatory activity. While the reciprocal synaptic circuits between TRN and sensory thalamic nuclei underlie the generation of sleep spindles, the mechanisms regulating slow (\u3c1 \u3eHz) forms of thalamic oscillations are poorly understood. Under in vitro conditions, in the absence of synaptic inputs, TRN neurons can generate slow oscillations in a cell-intrinsic manner. Activation of postsynaptic Group 1 metabotropic glutamate receptors (mGluR) leads to long-lasting plateau potentials thought to be mediated by both T-type calcium currents and calcium-activated nonselective cation currents (ICAN). However, the identity of ICAN and the possible contribution of thalamic circuits to slow rhythmic activity remain unclear. Using intracellular recordings of neurons in thalamic slices derived from adult male and female mice, I recorded slow forms of rhythmic activity in TRN neurons. Slow oscillations were driven by fast glutamatergic inputs from thalamic relay neurons, but did not require postsynaptic mGluR activation. For a significant minority of TRN neurons (33%), synaptic inputs or brief depolarizing current steps led to plateau potentials and persistent firing (PF), and in turn, resulted in persistent synaptic inhibition in postsynaptic relay neurons of the ventrobasal thalamus (VB). Pharmacological approaches indicated that plateau potentials were triggered by calcium influx through T-type calcium channels and mediated by calcium and voltage-dependent transient receptor potential melastatin 4 (TRPM4) channels. Taken together, my results suggest that thalamic circuits can generate slow oscillatory activity, mediated by an interplay of TRN-VB synaptic circuits that generate rhythmicity and TRN cell-intrinsic mechanisms that control PF and oscillation frequency

    Pharmacological activation of mGlu5 receptors with the positive allosteric modulator, VU0360172 modulates thalamic GABAergic transmission

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    Previous studies have shown that injection of the mGlu5 receptor positive allosteric modulator (PAM) VU0360172 into either the thalamus or somatosensory cortex markedly reduces the frequency of spike-and-wave discharges (SWDs) in the WAG/Rij model of absence epilepsy. Here we have investigated the effects of VU0360172 on GABA transport in the thalamus and somatosensory cortex, as possible modes of action underlying the suppression of SWDs. Systemic VU0360172 injections increase GABA uptake in thalamic synaptosomes from epileptic WAG/Rij rats. Consistent with this observation, VU0360172 could also enhance thalamic GAT-1 protein expression, depending on the dosing regimen. This increase in GAT-1 expression was also observed in the thalamus from non-epileptic rats (presymptomatic WAG/Rij and Wistar) and appeared to occur selectively in neurons. The tonic GABAA receptor current present in ventrobasal thalamocortical neurons was significantly reduced by VU0360172 consistent with changes in GAT-1 and GABA uptake. The in vivo effects of VU0360172 (reduction in tonic GABA current and increase in GAT-1 expression) could be reproduced in vitro by treating thalamic slices with VU0360172 for at least 1 hour and appeared to be dependent on the activation of PLC. Thus, the effects of VU0360172 do not require an intact thalamocortical circuit. In the somatosensory cortex, VU0360172 reduced GABA uptake but did not cause significant changes in GAT-1 protein levels. These findings reveal a novel mechanism of regulation mediated by mGlu5 receptors, which could underlie the powerful anti-absence effect of mGlu5 receptor enhancers in animal models
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