Behavioral correlates of an altered balance between synaptic and extrasynaptic GABAAergic inhibition in a mouse model.

S. T. Sinkkonen, E. Leppa, O. Y. Vekovischeva, O. Y. Vekovischeva, T. Moykkynen, A. M. Linden, W. Ogris, P. Wulff, W. Sieghart, A. Oberto, William Wisden, E. R. Korpi

    Research output: Contribution to journalArticle

    23 Citations (Scopus)

    Abstract

    GABA(A) receptors mediate fast phasic inhibitory postsynaptic potentials and participate in slower tonic extrasynaptic inhibition. Thy1alpha6 mice with ectopic forebrain expression of GABA(A) receptor alpha6 subunits exhibit increased extrasynaptic GABA(A) receptor-mediated background conductance and reduced synaptic GABA(A) receptor currents in hippocampal CA1 neurons [W. Wisden et al. (2002) Neuropharmacology 43, 530-549]. Here we demonstrate that isolated CA1 neurons of these mice showed furosemide-sensitivity of GABA-evoked currents, confirming the functional expression of alpha6 subunit. In addition, receptor autoradiography of the CA1 region of Thy1alpha6 brain sections revealed pharmacological features that are unique for alpha6betagamma2 and alpha6beta receptors. The existence of atypical alpha6beta receptors was confirmed after completely eliminating GABA(A) receptors containing gamma1, gamma2, gamma3 or delta subunits using serial immunoaffinity chromatography on subunit-specific GABA(A) receptor antibodies. Behaviourally, the Thy1alpha6 mice showed normal features with slightly enhanced startle reflex and struggle-escape behaviours. However, they were more sensitive to GABA(A) antagonists DMCM (shorter latency to writhing clonus) and picrotoxinin (shorter latency to generalized convulsions). Tiagabine, an antiepileptic GABA-uptake inhibitor that increases brain GABA levels, delayed picrotoxinin-induced convulsions at a low dose of 3.2 mg/kg in Thy1alpha6 mice, but not in control mice; however, the overall effect of higher tiagabine doses on the convulsion latency remained smaller in the Thy1alpha6 mice. Altered balance between extrasynaptic and synaptic receptors thus affects seizure sensitivity to GABAergic convulsants. Importantly, the increased extrasynaptic inhibition, even when facilitated in the presence of tiagabine, was not able fully to counteract enhanced seizure induction by GABA(A) antagonists.

    Original languageEnglish
    Pages (from-to)2168-2178
    Number of pages10
    JournalEuropean Journal of Neuroscience
    Volume20
    DOIs
    Publication statusPublished - 2004

    Keywords

    • epilepsy
    • phasic inhibition
    • tiagabine
    • tonic inhibition
    • TEMPORAL-LOBE EPILEPSY
    • TONIC INHIBITION
    • A RECEPTORS
    • GRANULE CELLS
    • NEURONAL EXCITABILITY
    • PYRAMIDAL NEURONS
    • SUBUNIT
    • BINDING
    • RAT
    • MICE

    Cite this

    Sinkkonen, S. T., Leppa, E., Vekovischeva, O. Y., Vekovischeva, O. Y., Moykkynen, T., Linden, A. M., Ogris, W., Wulff, P., Sieghart, W., Oberto, A., Wisden, W., & Korpi, E. R. (2004). Behavioral correlates of an altered balance between synaptic and extrasynaptic GABAAergic inhibition in a mouse model. European Journal of Neuroscience, 20, 2168-2178. https://doi.org/10.1111/j.1460-9568.2004.03684.x