Abnormality in GABAergic postsynaptic transmission associated with anxiety in mice with an mutation.

The homozygous () mouse, which shows hearing impairment, also exhibits anxiety accompanied by a reduction in cortical parvalbumin (PV)-positive GABAergic interneurons. Recently, a mutation in splicing factor Ser/Arg repetitive matrix 4 (Srrm4) was found in mice. However, the cellular consequences of the mutation for anxiety remain unknown. Here, we tested our hypothesis that mutant primarily affects interneurons through a cell-intrinsic pathology that leads to a reduction of interneurons and consequently causes anxiety. We found that the anxiety becomes apparent at 6 weeks of age in mice. However, in situ hybridization revealed that is not expressed in interneurons, but rather dominates in pyramidal neurons. In addition, the PV-positive GABAergic interneurons were not reduced in number in the cortex when anxiety became evident. However, electrophysiological abnormality of GABAergic transmission from interneurons was concomitantly present. Pharmacological blockage of GABA receptors revealed increased excitability in mice, although no gross change occurred in the expression of an -downstream gene, , which regulates chloride flux upon GABAergic transmission. These findings suggest that the -associated mutation mainly involves post-synaptic GABAergic transmission in the central nervous system, which may be associated with the anxiety phenotype in mice.