Morphometric changes in subcortical structures of the central auditory pathway in mice with bilateral nodular heterotopia

• BXD29-Tlr4lps−2J/J mice have smaller neurons in the MGN, regardless of sex.
• Female BXD29-Tlr4lps−2J/J mice have a shift toward larger neurons in the VCN.
• Female BXD29-Tlr4lps−2J/J mice have larger neurons in the DCN.

Malformations of cortical development (MCD) have been observed in human reading and language impaired populations. Injury-induced MCD in rodent models of reading disability show morphological changes in the auditory thalamic nucleus (medial geniculate nucleus; MGN) and auditory processing impairments, thus suggesting a link between MCD, MGN, and auditory processing behavior. Previous neuroanatomical examination of a BXD29 recombinant inbred strain (BXD29-Tlr4lps−2J/J) revealed MCD consisting of bilateral subcortical nodular heterotopia with partial callosal agenesis. Subsequent behavioral characterization showed a severe impairment in auditory processing—a deficient behavioral phenotype seen across both male and female BXD29-Tlr4lps−2J/J mice. In the present study we expanded upon the neuroanatomical findings in the BXD29-Tlr4lps−2J/J mutant mouse by investigating whether subcortical changes in cellular morphology are present in neural structures critical to central auditory processing (MGN, and the ventral and dorsal subdivisions of the cochlear nucleus; VCN and DCN, respectively). Stereological assessment of brain tissue of male and female BXD29-Tlr4lps−2J/J mice previously tested on an auditory processing battery revealed overall smaller neurons in the MGN of BXD29-Tlr4lps−2J/J mutant mice in comparison to BXD29/Ty coisogenic controls, regardless of sex. Interestingly, examination of the VCN and DCN revealed sexually dimorphic changes in neuronal size, with a distribution shift toward larger neurons in female BXD29-Tlr4lps−2J/J brains. These effects were not seen in males. Together, the combined data set supports and further expands the observed co-occurrence of MCD, auditory processing impairments, and changes in subcortical anatomy of the central auditory pathway. The current stereological findings also highlight sex differences in neuroanatomical presentation in the presence of a common auditory behavioral phenotype.