Maintenance of Thalamic Epileptiform Activity Depends on the Astrocytic Glutamate-Glutamine Cycle

Abstract

Bryant AS, Li B, Beenhakker MP, Huguenard JR. Maintenance of thalamic epileptiform activity depends on the astrocytic glutamateglutamine cycle. J Neurophysiol 102: 2880 -2888, 2009. First published September 9, 2009 doi:10.1152/jn.00476.2009. The generation of prolonged neuronal activity depends on the maintenance of synaptic neurotransmitter pools. The astrocytic glutamate-glutamine cycle is a major mechanism for recycling the neurotransmitters GABA and glutamate. Here we tested the effect of disrupting the glutamateglutamine cycle on two types of neuronal activity patterns in the thalamus: sleep-related spindles and epileptiform oscillations. In recording conditions believed to induce glutamine scarcity, epileptiform oscillations showed a progressive reduction in duration that was partially reversible by the application of exogenous glutamine (300 M). Blocking uptake of glutamine into neurons with ␣-(methylamino) isobutyric acid (5 mM) caused a similar reduction in oscillation duration, as did blocking neuronal GABA synthesis with 3-mercaptoproprionic acid (10 M). However, comparable manipulations did not affect sleep spindles. Together, these results support a crucial role for the glutamate-glutamine cycle in providing the neurotransmitters necessary for the generation of epileptiform activity and suggest potential therapeutic approaches that selectively reduce seizure activity but maintain normal neuronal activity.

A new mode of corticothalamic transmission revealed in the Gria4−/− model of absence epilepsy

“…In horizontal thalamic slices, electrical stimulation of the internal capsule evoked rhythmic activity in the thalamus (Fig. 2a), consistent with previous findings 21, 22 . Despite the absence of GluA4, the duration of evoked rhythmic activity was increased in thalamic slices from Gria4 –/– mice compared with wild type ( Gria4 –/– , 1.11 ± 0.16 s, n = 7 slices; wild type, 0.40 ± 0.18 s, n = 8 slices; P < 0.05; Fig.…”

“…We placed horizontal slices (400 μm) containing somatosensory thalamus in an interface chamber at 34 °C and superfused them at a rate of 2 ml min –1 with oxygenated artificial cerebrospinal fluid (ACSF) containing 126 mM NaCl, 2.5 mM KCl, 1.25 mM NaH 2 PO 4 , 2 mM MgCl 2 , 2 mM CaCl 2 , 26 mM NaHCO 3 and 10 mM glucose, equilibrated with 95% O 2 and 5% CO 2 , pH 7.4, supplemented with 0.3 mM glutamine 21 . We obtained extracellular multiunit field recordings with monopolar tungsten microelectrodes (50–100 kΩ, FHC) placed in VB thalamus and in nRT.…”

Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling

“…Our present results suggest a cellular mechanism for this effect in the nRT: a decrease in synaptic inhibition as reflected in decreased sIPSC duration, owing to a loss of endozepine signaling, and reduced sIPSC frequency. The development of SWD activity and absence seizures as a consequence of FC treatment is thus consistent with the hypothesized role for intra-nRT inhibition in decreasing thalamocortical oscillatory circuit activity (24), although other nonendozepine actions, such as reduced glutamate uptake and recycling (45), also could contribute to seizures, as could effects of astrocytic disruption in regions outside of the thalamus.…”

Regulation of Thalamic and Cortical Network Synchrony by Scn8a

“…400 μm thick horizontal slices containing RT and somatosensory (TC) thalamus were prepared as previously described (Huguenard and Prince, 1994). Recordings were performed in a humidified oxygenated interface chamber at 34°C and superfused at a rate of 3 mL min −1 with oxygenated ACSF (indicated above), supplemented with 0.3 mM glutamine (Bryant et al, 2009). Thalamic oscillations were evoked by applying square current pulses (250 μA, 50 μs duration) to the internal capsule (i.c.)…”