The role of Grn in the development of mouse cochlear nucleus synapses

Progranulin (encoded by Grn) is a multifunctional glycoprotein implicated in neuronal survival and synapse function, yet its role in central auditory circuit development remains unclear. In this study, we investigated the role of Grn in mouse cochlear nucleus (CN) synapse development. Grn^-/- and Grn^+/+ mice were used in this study. Grn (Progranulin) expression was examined by reverse transcription PCR and immunofluorescence. Neuronal density and synaptic puncta expression within the CN were analyzed using immunofluorescence labeling and quantitative image analysis. Auditory function was assessed by measuring auditory brainstem responses (ABRs) to evaluate hearing thresholds, latencies, and amplitudes. ABR testing revealed that Grn^-/- mice exhibited normal hearing thresholds and ABR wave-II latencies compared to Grn^+/+ controls, indicating that the overall hearing sensitivity was largely preserved. However, Grn^-/- mice showed a significant reduction in ABR wave-II amplitudes, suggesting impaired synaptic efficacy or connectivity within the CN. Consistent with this, immunofluorescence analysis demonstrated a marked decrease in synaptic puncta immunofluorescence density, including both presynaptic and postsynaptic markers, in the CN of Grn^-/- mice. Notably, CN neuronal numbers remained unchanged, indicating that the synaptic deficits were not due to neuronal loss. Together, these findings identify a previously unrecognized role of Grn in CN synapses during postnatal development up to 4 weeks old. The results further suggest that Grn deficiency leads to central auditory synaptopathy, providing insight into the molecular mechanisms underlying auditory synaptic dysfunction associated with Grn loss.