title: Linking Immature Auditory Processing with an Autism Phenotype in the BdnfPax2 KO Mouse Model
Creators: name: Hess, Morgan Elizabeth
Publisher: name: Universität Tübingen
Year: 2024
Subjects: subject: 500
subject: 570

description: Hearing and cognition are tightly bound together in a link that enables complex processes such as language learning and communication. The establishment of this link critically depends on proper development of the ascending auditory pathway and its connections to higher order regions. Neural development occurs hierarchically in terms of complexity, meaning that mature sensory processing is a prerequisite for mature cognitive processing. Because sensory system development requires a series of maturational events occurring in sequence from the peripheral to the central nervous system, we hypothesized that a disruption in peripheral processes early in development can cascade along the ascending pathway and result in higher level cognitive deficits. To examine the link between immature sensory processing and higher-level cognitive processes, we used a model in which brain-derived neurotrophic factor (Bdnf) was deleted from paired box gene 2 (Pax2)-expressing interneurons (INs) that migrate to lower brain regions, including the auditory brainstem, and the cochlea (“BdnfPax2 KO”). As BDNF has been suggested to trigger neuronal maturation, this model is assumed to result in a specific subset of INs in the peripheral auditory system remaining in an immature state. This deletion affected not only the hearing of BdnfPax2 KO mice but also higher-level cognitive processes, leading to social interaction deficits and stereotypic behavior—both core diagnostic criteria of autism spectrum disorder (ASD). We therefore here aimed to further characterize the phenotype of BdnfPax2 KO mice on a functional, molecular, and structural level, and found that these mice exhibited neural response characteristics, excitatory and inhibitory molecular markers, and dendritic spine morphology consistent with other animal models of ASD. Having validated a phenotype strongly consistent with ASD in this model, we then examined how the immature sensory processing of BdnfPax2 KO mice led to this central phenotype. We discovered that a specific class of auditory nerve fibers remained under-responsive in these mice, which may reflect an immature state resulting from insufficient inhibitory shaping during development. We speculate that this persisting immaturity in the periphery interfered with the maturation of more complex, cognitive processes and resulted in an ASD phenotype. The absence of a known disease mechanism causing ASD has hindered the search for effective treatment options. Thus, having identified a putative underlying neural mechanism in our model, we used two different treatment approaches tailored to nudge the phenotype of adult BdnfPax2 KO mice back to a physiological state. First, a pharmaceutical approach was used to target the more central aspects of the phenotype, but it yielded no therapeutic benefit for BdnfPax2 KO mice. We propose that this is because the central aspects of the phenotype are a secondary effect to the underlying peripheral deficit. Thus, the next treatment approach was a sensory-specific enrichment paradigm that targeted the more peripheral aspects of the phenotype. This treatment resulted in a reversal of the hearing phenotype of BdnfPax2 KO mice but still did not recover cognitive aspects of the phenotype. These findings indicate that, while more peripheral and comparatively simple sensory processing can be rescued during adulthood, more complex central processes cannot be. This would necessitate an early intervention strategy for developmental disorders such as ASD, using treatments that target the underlying peripheral, sensory deficits.