Aberrant GABAA Receptor-Mediated Inhibition in Cortico-Thalamic Networks of Succinic Semialdehyde Dehydrogenase Deficient Mice

Adam C Errington,Vincenzo Crunelli,K Michael Gibson,David W Cope,Mark P Mattson

doi:10.1371/journal.pone.0019021

Adam C Errington, Vincenzo Crunelli + Show 3 more

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https://doi.org/10.1371/journal.pone.0019021

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Abstract

Aberrant γ-aminobutyric acid type A (GABAA) receptor-mediated inhibition in cortico-thalamic networks remains an attractive mechanism for typical absence seizure genesis. Using the whole-cell patch clamp technique we examined ‘phasic’ and ‘tonic’ GABAA inhibition in thalamocortical neurons of somatosensory (ventrobasal, VB) thalamus, nucleus reticularis thalami (NRT) neurons, and layer 5/6 pyramidal neurons of the somatosensory (barrel) cortex of succinic semialdehyde dehydrogenase (SSADH) knock-out (SSADH−/−) mice that replicate human SSADH deficiency and exhibit typical absence seizures. We found increased sIPSC frequency in both VB and NRT neurons and larger sIPSC amplitude in VB neurons of SSADH−/− mice compared to wild-type animals, demonstrating an increase in total phasic inhibition in thalamus of SSADH−/− mice. mIPSCs in both VB and NRT neurons were no different between genotypes, although there remained a trend toward more events in SSADH−/− mice. In cortical layer 5/6 pyramidal neurons, sIPSCs were fewer but larger in SSADH−/− mice, a feature retained by mIPSCs. Tonic currents were larger in both thalamocortical neurons and layer 5/6 pyramidal neurons from SSADH−/− mice compared to WTs. These data show that enhanced, rather than compromised, GABAA receptor-mediated inhibition occurs in cortico-thalamic networks of SSADH−/− mice. In agreement with previous studies, GABAA receptor-mediated inhibitory gain-of-function may be a common feature in models of typical absence seizures, and could be of pathological importance in patients with SSADH deficiency.

Highlights

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessively inherited disorder which, when compared with other neurometabolic disorders, is relatively common with approximately 400 identified cases worldwide [1]
(3 mM) to block ionotropic glutamate receptors and isolate GABAA receptor mediated currents (Cope et al, 2009), sIPSCs were readily apparent in thalamocortical neurons of the VB thalamus from both WT (n = 11 cells) and SSADH2/2 (n = 9 cells) mice (Fig. 1A and Table 1), as described previously
There was a significant difference in the distribution of inter-inhibitory post-synaptic currents (IPSCs) intervals between WT and SSADH2/2 mice (P,0.001), so that shorter inter-IPSC intervals were more prevalant in SSADH2/2 mice (Fig. 1B)

Summary

Introduction

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessively inherited disorder which, when compared with other neurometabolic disorders, is relatively common with approximately 400 identified cases worldwide [1]. SSADH deficient mice were developed that replicate the GHB and GABA accumulation exhibited in humans, and have a strikingly similar epileptic phenotype [1,6,7]. Homozygous SSADH knock-out (SSADH2/2) mice display typical absence seizures that appear at the beginning of the third postnatal week, evolve into myoclonic and generalized convulsive seizures, and progress to lethal status epilepticus [6,8,9]. These mice are a valuable tool in examining the pathological cellular mechanisms underlying seizure genesis in SSADH deficiency

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