The circuitry of atypical absence seizures in GABABR1a transgenic mice

The objective of the current study was to determine the origin of the slow spike and wave discharges (SSWD) in the transgenic mouse with postnatal over-expression of the GABAB receptor subunit R1a (GABABR1atg), a mutant animal with a characteristic phenotype consisting of atypical absence seizures and cognitive dysfunction. Using simultaneous electrocorticographic (ECoG) recordings from cortical and depth electrodes in freely moving GABABR1atg mice, we showed that the SSWD in this model of atypical absence seizures arise exclusively from midline thalamus (MT), reticular nucleus of the thalamus (nRT), and the CA1 region of the hippocampus. Lesioning of the MT and nRT with ibotenic acid abolished SSWD. Microinjection of the GABAB receptor agonist, (−) baclofen, into MT and nRT exacerbated, and the GABABR antagonist, CGP 35348 abolished, SSWD in the GABABR1atg mice. These data suggest that the nRT and MT are necessary for the generation of SSWD in the GABABR1atg model of atypical absence seizures, and indicate that GABABR-mediated mechanisms within thalamus are necessary for the genesis of SSWD in atypical absence seizures. A putative cortico-thalamo-hippocampal circuit is proposed to explain the unique electrographic findings, ictal behavior, pharmacology, and impairment of cognition that characterize atypical absence seizures.