Altered intrathalamic GABAA neurotransmission in a mouse model of a human genetic absence epilepsy syndrome.

We previously demonstrated that heterozygous deletion of Gabra1, the mouse homolog of the human absence epilepsy gene that encodes the GABAA receptor (GABAAR) α1 subunit, causes absence seizures. We showed that cortex partially compensates for this deletion by increasing the cell surface expression of residual α1 subunit and by increasing α3 subunit expression. Absence seizures also involve two thalamic nuclei: the ventrobasal (VB) nucleus, which expresses only the α1 and α4 subtypes of GABAAR α subunits, and the reticular (nRT) nucleus, which expresses only the α3 subunit subtype. Here, we found that, unlike cortex, VB exhibited significantly reduced total and synaptic α1 subunit expression. In addition, heterozygous α1 subunit deletion substantially reduced miniature inhibitory postsynaptic current (mIPSC) peak amplitudes and frequency in VB. However, there was no change in the expression of the extrasynaptic α4 or δ subunits in VB and, unlike other models of absence epilepsy, no change in tonic GABAAR currents. Although heterozygous α1 subunit knockout increased α3 subunit expression in medial thalamic nuclei, it did not alter α3 subunit expression in nRT. However, it did enlarge the presynaptic vesicular inhibitory amino acid transporter puncta and lengthen the time constant of mIPSC decay in nRT. We conclude that increased tonic GABAA currents are not necessary for absence seizures. In addition, heterozygous loss of α1 subunit disinhibits VB by substantially reducing phasic GABAergic currents and surprisingly, it also increases nRT inhibition by prolonging phasic currents. The increased inhibition in nRT likely represents a partial compensation that helps reduce absence seizures.