Sex-specific and age-related progression of auditory neurophysiological deficits in the Cln3 mouse model of Batten disease

CLN3 disease is a prevalent form of Neuronal Ceroid Lipofuscinosis (NCL) caused by inherited mutations in the CLN3 gene, with symptoms such as vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates neurological assessment of brain pathophysiology underlying cognitive decline, while the small number of CLN3 mutation cases in humans hinders the study of sex differences. Building on our recent progress in assessing auditory neurophysiological changes in CLN3 patients, we developed a parallel approach using electroencephalography arrays in Cln3 knockout (Cln3-/-) mice to investigate the longitudinal progression of auditory processing deficits in both sexes. We employed a duration mismatch negativity (MMN) paradigm, similar to that used in our CLN3 patient studies, to assess the automatic detection of pattern changes in a sequence of stimuli. Wild-type mice of both sexes showed robust duration MMN responses when assessed longitudinally in the same subjects from 3 to 9 months of age. In contrast, female Cln3-/- mice developed consistent MMN deficits throughout this age range, while male Cln3-/- mice exhibited MMN deficits at younger ages that were mitigated at older ages. Analyses of auditory brainstem responses indicate that MMN abnormalities in Cln3-/- mice are not due to peripheral hearing loss. Instead, these deficits originate centrally from sex-specific and age-related changes in auditory evoked potentials elicited by standard and deviant stimuli. Our findings reveal a sex-specific progression of central auditory processing deficits in Cln3-/- mice, supporting auditory duration MMN as a translational neurophysiological biomarker for mechanistic studies and therapeutic development. Significance StatementCLN3 disease is an inherited neurodegenerative disorder with progressive decline in cognitive functioning and verbal abilities. The neuropathophysiological mechanisms underlying this decline remain poorly understood, highlighting the urgent need for objective neurological biomarkers to advance mechanistic insights and therapeutic development. Our identification of central auditory processing and change detection deficits in Cln3-/- mice, mirroring findings from our recent studies in CLN3 patients, validates auditory MMN as a translational neurophysiological biomarker bridging pre-clinical and clinical research. Moreover, our discovery of sex-specific, non-linear progression of MMN deficits emphasizes the necessity of developing disease management strategies tailored to each sex. This finding also provides a foundation for investigating both pathogenic and compensatory neural mechanisms to inform the development of individualized treatments.