Aberrant GABA(A) receptor-mediated inhibition in cortico-thalamic networks of succinic semialdehyde dehydrogenase deficient mice.

Abstract

Aberrant γ-aminobutyric acid type A (GABA(A)) 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' GABA(A) 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, GABA(A) receptor-mediated inhibition occurs in cortico-thalamic networks of SSADH(-/-) mice. In agreement with previous studies, GABA(A) 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.

• Authors: Adam C Errington, K Michael Gibson, Vincenzo Crunelli, David W Cope
• Journal: PloS one (PLoS One) Vol. 6 Issue 4 Pg. e19021 (Apr 19 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21526163 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphinic Acids
• Propanolamines
• Receptors, GABA-A
• Receptors, GABA-B
• CGP 55845A
• Succinate-Semialdehyde Dehydrogenase

Topics

• Animals
• Cerebral Cortex (drug effects, physiology)
• Female
• Humans
• In Vitro Techniques
• Inhibitory Postsynaptic Potentials (drug effects, physiology)
• Ion Channel Gating (drug effects, physiology)
• Male
• Mice
• Nerve Net (drug effects, physiology)
• Neural Inhibition (drug effects, physiology)
• Neurons (drug effects, metabolism)
• Phosphinic Acids (pharmacology)
• Propanolamines (pharmacology)
• Pyramidal Cells (drug effects, metabolism)
• Receptors, GABA-A (metabolism)
• Receptors, GABA-B (metabolism)
• Succinate-Semialdehyde Dehydrogenase (deficiency, metabolism)
• Thalamus (drug effects, physiology)