Selective loss of AMPA receptors at corticothalamic synapses in the epileptic stargazer mouse

Abstract

Absence seizures are common in the stargazer mutant mouse. The mutation underlying the epileptic phenotype in stargazers is a defect in the gene encoding the normal expression of the protein stargazin. Stargazin is involved in the membrane trafficking and synaptic targeting of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at excitatory glutamatergic synapses. Thus, the genetic defect in the stargazer results in a loss of AMPARs and consequently, excitation at glutamatergic synapses. Absence seizures are known to arise in thalamocortical networks. In the present study we show for the first time, using Western blot analysis and quantitative immunogold cytochemistry, that in the epileptic stargazer mouse, there is a global loss of AMPAR protein in nucleus reticularis (RTN) and a selective loss of AMPARs at corticothalamic synapses in inhibitory neurons of the RTN thalamus. In contrast, there is no significant loss of AMPARs at corticothalamic synapses in excitatory relay neurons in the thalamic ventral posterior (VP) region. The findings of this study thus provide cellular and molecular evidence for a selective regional loss of synaptic AMPAR within the RTN that could account for the loss of function at these inhibitory neuron synapses, which has previously been reported from electrophysiological studies. The specific loss of AMPARs at RTN but not relay synapses in the thalamus of the stargazer, could contribute to the absence epilepsy phenotype by altering thalamocortical network oscillations. This is supported by recent evidence that loss of glutamate receptor subunit 4 (GluA4) (the predominant AMPAR-subtype in the thalamus), also leads to a specific reduction in strength in the cortico-RTN pathway and enhanced thalamocortical oscillations, in the Gria4(-/-) model of absence epilepsy. Thus further study of thalamic changes in these models could be important for future development of drugs targeted to absence epilepsy.