Distinct Auditory Thalamocortical Pathologies Underlie Emerging Neurophysiological Dysfunction in a Cln3 Mouse Model...

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• CLN3 disease, a form of Neuronal Ceroid Lipofuscinoses (NCLs), leads to cognitive and language decline.
• Lysosomal storage material accumulation, due to CLN3 gene mutations, is a key pathological feature.
• Previous work identified auditory duration mismatch negativity (MMN) deficits in CLN3 patients and Cln3-/- mice.

Purpose of the Study:

• To investigate the central auditory system dysfunction in Cln3-/- mice.
• To integrate neuropathological findings with electrophysiological data to understand auditory deficits.
• To identify the anatomical and neurophysiological basis of auditory processing impairments in CLN3 disease.

Main Methods:

• Immunohistochemical mapping of lysosomal storage using Subunit C of Mitochondrial ATP Synthase (SCMAS).
• Analysis of auditory evoked potentials (AEPs) using electroencephalography (EEG).
• Integration of histological and EEG data to correlate pathology with function in the auditory thalamocortical circuit.

Main Results:

• SCMAS accumulation occurred in an age- and sex-dependent manner across the auditory thalamocortical circuit.
• Cln3-/- mice showed age- and sex-dependent alterations in AEPs compared to wild-type controls.
• Auditory thalamocortical SCMAS accumulation significantly predicted variations in AEP responses, particularly the N1 component.

Conclusions:

• Auditory neurophysiological deficits in Cln3-/- mice are linked to specific lysosomal storage pathology within the auditory thalamocortical circuit.
• The findings highlight age- and sex-dependent circuit vulnerability in CLN3 disease.
• This study provides a framework for developing translational neurophysiological biomarkers for CLN3 disease.