GABA Affinity Shapes IPSCs in Thalamic Nuclei

Schofield, Claude M.; Huguenard, John R.

doi:10.1523/jneurosci.0377-07.2007

Cited by 49 publications

(52 citation statements)

References 59 publications

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“…Synaptic GABA A -Rs in VB neurons are thought to be mainly the ␣ 1 ␤ 2 ␥ 2 subtype (Pirker et al, 2000;Jia et al, 2005). The mean time constant of IPSCs recorded from VB relay neurons (16.2 Ϯ 1.2 ms, n ϭ 22) is much smaller than that of RTN neurons, in agreement with previous studies (Zhang et al, 1997;Huntsman and Huguenard, 2000;Schofield and Huguenard, 2007). At low concentrations (0.1 M), eszopiclone did not change any properties of spontaneous IPSCs in VB neurons.…”

Section: Downloaded Fromsupporting

confidence: 90%

The Modulation of Synaptic GABAA Receptors in the Thalamus by Eszopiclone and Zolpidem

Fan¹,

Goldstein²,

Harrison³

2009

The Journal of Pharmacology and Experimental Therapeutics

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Eszopiclone (Lunesta; Sepracor, Marlborough, MA) and zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)-imidazo(1,2-a)pyridine-3-acetamide] are among the most commonly prescribed hypnotics in use in the United States. The thalamus plays a pivotal role in sleep regulation and rhythmicity. Two distinct subtypes of synaptic GABA A receptors (GABA A -Rs), ␣ 1 ␤ 2 ␥ 2 and ␣ 3 ␤ 3 ␥ 2 , are expressed in thalamocortical relay neurons and in interneurons of the RTN (reticular thalamic nucleus), respectively. Thalamocortical neurons also express extrasynaptic GABA A -Rs composed of ␣ 4 ␤ 2 ␦ subunits. In this study, we compared the effects of eszopiclone and zolpidem on miniature inhibitory postsynaptic currents (IPSCs), spontaneous IPSCs, and tonic inhibition in the mouse thalamus. Eszopiclone (0.1-1 M) slowed the decay phase of IPSCs recorded from RTN neurons, whereas zolpidem was less effective and increased the decay time constant only at Ն0.3 M. IPSCs of RTN neurons were more sensitive to eszopiclone than zolpidem at all concentrations tested. On the other hand, IPSCs of relay neurons in the ventrobasal nucleus (VB) were more sensitive to zolpidem than eszopiclone. Zolpidem (0.1-1 M) prolonged the decay of IPSCs from VB neurons, whereas eszopiclone increased the decay time constant only at Ն0.3 M. Neither of these two hypnotics affected tonic inhibition in relay neurons. Our results demonstrate that eszopiclone has greater efficacy at synaptic GABA A -Rs of RTN neurons than in relay neurons, whereas zolpidem exerts bigger effects on relay neurons than RTN neurons. This distinct pattern of activity on thalamic neurons may contribute to some of the observed differences in the clinical effects of these two hypnotics.

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Section: Downloaded Fromsupporting

confidence: 90%

The Modulation of Synaptic GABAA Receptors in the Thalamus by Eszopiclone and Zolpidem

Fan¹,

Goldstein²,

Harrison³

2009

The Journal of Pharmacology and Experimental Therapeutics

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“…The PPR at 50 ms was reduced from 1.00 Ϯ 0.15 at P1-P5 (n ϭ 16) to 0.65 Ϯ 0.04 at P7-P9 (n ϭ 17), suggesting a presynaptic change of GABA release. Finally, the IPSC duration that is related to the GABA A R characteristics (Zhang et al, 1997;Schofield and Huguenard, 2007) was significantly increased between P1 and P9 (Table 1).…”

Section: Postnatal Development Of the Thalamic Inhibitory Feedback Loopmentioning

confidence: 98%

Early Development of the Thalamic Inhibitory Feedback Loop in the Primary Somatosensory System of the Newborn Mice

Evrard¹,

Ropert²

2009

J. Neurosci.

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Spontaneous neuronal activity plays an important role during the final development of the brain circuits and the formation of the primary sensory maps. In young rats, spindle bursts have been recorded in the primary somatosensory cortex. They are correlated with spontaneous muscle twitches and occur before active whisking. They bear similarities with the spindles recorded in adult brain that occur during early stages of sleep and rely on a thalamic feedback loop between the glutamatergic nucleus ventroposterior medialis (nVPM) and the GABAergic nucleus reticularis thalami (nRT). However, whether a functional nVPM-nRT loop exists in newborn rodents is unknown. We studied the reciprocal synaptic connections between nVPM and nRT in thalamic acute slices from mice from birth [postnatal day 0 (P0)] until P9. We first demonstrated that nVPM-to-nRT EPSCs could be distinguished from corticothalamic EPSCs by their inhibition by 5-HT attributable to the transient expression of functional presynaptic serotonin 1B receptors. The nVPM-to-nRT EPSCs and nRT-to-nVPMIPSCs were both detected the first day after birth; their amplitude near 2 nS was relatively stable until P5. At P6 -P7, there was a rapid and simultaneous increase of both nVPM-to-nRT EPSCs and nRT-to-nVPM IPSCs that reached 8 and 9 nS, respectively. Our results show that the thalamic synapses implicated in spindle activity are functional shortly after birth, suggesting that they could already generate spindles during the first postnatal week. Our results also suggest an inhibitory action of 5-HT on the spindle bursts of the newborn mice.

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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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GABA Affinity Shapes IPSCs in Thalamic Nuclei

Cited by 49 publications

References 59 publications

The Modulation of Synaptic GABAA Receptors in the Thalamus by Eszopiclone and Zolpidem

The Modulation of Synaptic GABAA Receptors in the Thalamus by Eszopiclone and Zolpidem

Early Development of the Thalamic Inhibitory Feedback Loop in the Primary Somatosensory System of the Newborn 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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