SUMMARYPurpose: Absence seizures, also known as petit mal seizures, arise from disruptions within the cortico-thalamocortical network. Interconnected circuits within the thalamus consisting of inhibitory neurons of the reticular thalamic nucleus (RTN) and excitatory relay neurons of the ventral posterior (VP) complex, generate normal intrathalamic oscillatory activity. The degree of synchrony in this network determines whether normal (spindle) or pathologic (spike wave) oscillations occur; however, the cellular and molecular mechanisms underlying absence seizures are complex and multifactorial and currently are not fully understood. Recent experimental evidence from rodent models suggests that regional alterations in c-aminobutyric acid (GABA)ergic inhibition may underlie hypersynchronous oscillations featured in absence seizures. The aim of the current study was to investigate whether region-specific differences in GABA A receptor (GABA A R) subunit expression occur in the VP and RTN thalamic regions in the stargazer mouse model of absence epilepsy where the primary deficit is in a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression. Methods: Immunofluorescence confocal microscopy and semiquantitative Western blot analysis were used to investigate region-specific changes in GABA A R subunits in the thalamus of the stargazer mouse model of absence epilepsy to determine whether changes in GABAergic inhibition could contribute to the mechanisms underlying seizures in this model of absence epilepsy. Key Findings: Immunofluorescence confocal microscopy revealed that GABA A R a1 and b2 subunits are predominantly expressed in the VP, whereas a3 and b3 subunits are localized primarily in the RTN. Semiquantitative Western blot analysis of VP and RTN samples from epileptic stargazers and their nonepileptic littermates showed that GABA A R a1 and b2 subunit expression levels in the VP were significantly increased (a1: 33%, b2: 96%) in epileptic stargazers, whereas a3 and b3 subunits in the RTN were unchanged in the epileptic mice compared to nonepileptic control littermates. Significance: These findings suggest that region-specific differences in GABA A R subunits in the thalamus of epileptic mice, specifically up-regulation of GABA A Rs in the thalamic relay neurons of the VP, may contribute to generation of hypersynchronous thalamocortical activity in absence seizures. Understanding region-specific differences in GABA A R subunit expression could help elucidate some of the cellular and molecular mechanisms underlying absence seizures and thereby identify targets by which drugs can modulate the frequency and severity of epileptic seizures. Ultimately, this information could be crucial for the development of more specific and effective therapeutic drugs for treatment of this form of epilepsy.
Absence seizures are known to originate from disruptions within the corticothalamocortical network; however, the precise underlying cellular and molecular mechanisms that induce hypersynchronicity and hyperexcitability are debated and likely to be complex and multifactorial. Recent studies implicate impaired thalamic GABAergic inhibition as a common feature in multiple animal models of absence epilepsy, including the well-established stargazer mouse model. Recently, we demonstrated region-specific increases in the whole tissue and synaptic levels of GABAA receptor (GABAAR) subunits α1 and β2, within the ventral posterior region of the thalamus in adult epileptic stargazer mice compared with nonepileptic control littermates. The objective of this study was to investigate whether such changes in GABAAR subunits α1 and β2 can be observed before the initiation of seizures, which occur around postnatal (PN) days 16-18 in stargazers. Semiquantitative western blotting was used to analyze the relative tissue level expression of GABAAR α1 and β2 subunits in the thalamus of juvenile stargazer mice compared with their nonepileptic control littermates at three different time points before the initiation of seizures. We show that there is a statistically significant increase in the expression of α1 and β2 subunits in the thalamus of stargazer mice, at the PN7-9 stage, compared with the control littermates, but not at PN10-12 and PN13-15 stages. These results suggest that an aberrant expression of GABAAR subunits α1 and β2 in the stargazers does not occur immediately before seizure onset and therefore is unlikely to directly contribute to the initiation of absence seizures.
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