Abnormality in GABAergic postsynaptic transmission associated with anxiety in Bronx waltzer mice with an Srrm4 mutation

Abstract

The homozygous Bronx waltzer (bv) 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 bv mice. However, the cellular consequences of the Srrm4 mutation for anxiety remain unknown. Here, we tested our hypothesis that bv 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 bv/bv mice. However, in situ hybridization revealed that Srrm4 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 bv/bv cortex when anxiety became evident. However, electrophysiological abnormality of GABAergic transmission from interneurons was concomitantly present. Pharmacological blockage of GABA_A receptors revealed increased excitability in bv/bv mice, although no gross change occurred in the expression of an Srrm4-downstream gene, Kcc2, which regulates chloride flux upon GABAergic transmission. These findings suggest that the bv-associated Srrm4 mutation mainly involves post-synaptic GABAergic transmission in the central nervous system, which may be associated with the anxiety phenotype in bv/bv mice.