Distinct Auditory Thalamocortical Pathologies Underlie Emerging Neurophysiological Dysfunction in a Cln3 Mouse Model of Batten Disease

Abstract

CLN3 disease, the most common form of the Neuronal Ceroid Lipofuscinoses (NCLs), causes progressive cognitive decline and language impairment in humans. A pathological hallmark is the accumulation of storage material within neuronal lysosomes resulting from mutations in the CLN3 gene. We previously identified parallel deficits in auditory duration mismatch negativity (MMN), an electroencephalography (EEG)-based marker of auditory change detection, in individuals with CLN3 disease and in Cln3-/- mice. MMN-dependent auditory change detection relies on sensory-memory comparison mechanisms. However, the anatomical and neurophysiological substrates underlying this response in CLN3 disease remain unclear. Here, we investigated central auditory dysfunction in Cln3-/- mice by integrating immunohistochemical mapping of lysosomal storage pathology, using the canonical marker Subunit C of Mitochondrial ATP Synthase (SCMAS), with EEG analysis of auditory evoked potentials (AEPs). Neuropathological analyses revealed age-dependent and sex-divergent SCMAS accumulation across the auditory thalamocortical circuit, including the excitatory auditory thalamus, the inhibitory thalamic reticular nucleus, and the primary auditory cortex. In parallel, Cln3-/- mice exhibited age- and sex-dependent alterations in AEPs relative to wild-type controls. Importantly, an integrated measure of auditory thalamocortical SCMAS accumulation accounted for a substantial portion of age- and sex-matched variation in AEP responses, with stronger associations for the early N1 component than the later MMN component. Together, these findings link age-dependent and sex-divergent auditory neurophysiological deficits to region-specific lysosomal storage pathology within the auditory thalamocortical circuit in the Cln3-/- mouse model. This integrated functional-anatomical framework provides insight into circuit vulnerability and supports the development of translational neurophysiological biomarkers for CLN3 disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/729359v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8dc148org.highwire.dtl.DTLVardef@8c918borg.highwire.dtl.DTLVardef@a7483dorg.highwire.dtl.DTLVardef@77d171_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISCMAS accumulates across the auditory thalamocortical circuit in Cln3-/- mice C_LIO_LIAccumulation shows distinct age- and sex-dependent regional trajectories C_LIO_LICln3-/- mice exhibit progressive alterations in auditory evoked potentials C_LIO_LIThalamic pathology is strongly associated with the early auditory N1 response C_LIO_LIHistology-EEG integration links circuit pathology to auditory dysfunction C_LI