Non-neuronal, slow GABA signalling in the ventrobasal thalamus targets δ-subunit-containing GABAA receptors

Cristina Jiménez-González,David W Cope,H R Parri,Tiina Pirttimaki

doi:10.1111/j.1460-9568.2011.07645.x

Cristina Jiménez-González, David W Cope + Show 2 more

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https://doi.org/10.1111/j.1460-9568.2011.07645.x

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Abstract

The rodent ventrobasal (VB) thalamus contains a relatively uniform population of thalamocortical (TC) neurons that receive glutamatergic input from the vibrissae and the somatosensory cortex, and inhibitory input from the nucleus reticularis thalami (nRT). In this study we describe γ-aminobutyric acid (GABA)A receptor-dependent slow outward currents (SOCs) in TC neurons that are distinct from fast inhibitory postsynaptic currents (IPSCs) and tonic currents. SOCs occurred spontaneously or could be evoked by hypo-osmotic stimulus, and were not blocked by tetrodotoxin, removal of extracellular Ca2+ or bafilomycin A1, indicating a non-synaptic, non-vesicular GABA origin. SOCs were more common in TC neurons of the VB compared with the dorsal lateral geniculate nucleus, and were rarely observed in nRT neurons, whilst SOC frequency in the VB increased with age. Application of THIP, a selective agonist at δ-subunit-containing GABAA receptors, occluded SOCs, whereas the benzodiazepine site inverse agonist β-CCB had no effect, but did inhibit spontaneous and evoked IPSCs. In addition, the occurrence of SOCs was reduced in mice lacking the δ-subunit, and their kinetics were also altered. The anti-epileptic drug vigabatrin increased SOC frequency in a time-dependent manner, but this effect was not due to reversal of GABA transporters. Together, these data indicate that SOCs in TC neurons arise from astrocytic GABA release, and are mediated by δ-subunit-containing GABAA receptors. Furthermore, these findings suggest that the therapeutic action of vigabatrin may occur through the augmentation of this astrocyte–neuron interaction, and highlight the importance of glial cells in CNS (patho) physiology.

Highlights

Introduction cAminobutyric acid (GABA)ergic signalling in the thalamus is central to controlling the relay of sensory information to the cortex, and in shaping behavioural state-dependentphysiological cortico-thalamocortical (TC) oscillations (Huguenard & McCormick, 2007)
We investigated spontaneous slow outward current (sSOC) frequency at different ages in TC neurons of the VB. sSOC frequency was significantly lower in TC neurons at P10 compared with P20 (P10 – 0.30 ± 0.01 ⁄ min, n = 19 neurons; P20 – 0.40 ± 0.05 ⁄ min, n = 11 neurons; P < 0.01; Fig. 3C). evoked slow outward current (eSOC) frequency in response to hypo-osmotic stimulation was similar to sSOC frequency in neurons from P10 animals (0.49 ± 0.10 ⁄ min, n = 6 neurons), whereas the incidence of eSOCs was greater than sSOCs in neurons from P20 animals (2.35 ± 0.63 ⁄ min, n = 8 neurons). eSOC frequency was significantly different between the two ages (P < 0.01; Fig. 3B)
Alternate non-synaptic neuronal c-aminobutyric acid (GABA) release mechanisms have been demonstrated (Koch & Magnusson, 2009), and in the dorsal lateral geniculate nucleus (dLGN) GABA can be released from interneuron dendrites (Acuna-Goycolea et al, 2008), the absence of interneurons in the VB thalamus, coupled to the fact that dendritic GABA release is vesicular and dependent on extracellular Ca2+, precludes this mechanism in accounting for our observations (Isaacson, 2001)

Summary

Introduction

Introduction cAminobutyric acid (GABA)ergic signalling in the thalamus is central to controlling the relay of sensory information to the cortex, and in shaping behavioural state-dependent (patho)physiological cortico-thalamocortical (TC) oscillations (Huguenard & McCormick, 2007). We describe spontaneous, transient, non-synaptic slow outward currents (SOC) in TC neurons that are generated by the release of GABA from astrocytes.

Results

Conclusion