2024 Scholars' Research Symposium Abstract: Sex-Split Analysis of Pathology and Motor-Behavioral Outcomes in a Mouse Model Of CLN8-Batten Disease.

Abstract

Introduction: CLN8-Batten disease is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 result in characteristic Batten disease symptoms and brain-wide pathology including accumulation of lysosomal storage material, gliosis, and neurodegeneration. Recent investigations of other subtypes of Batten disease (CLN1, CLN3, CLN6) have emphasized the influence of biological sex on disease and treatment outcomes; however, little is known about sex differences in the CLN8 subtype.

Methods: To determine the impact of sex on CLN8 disease burden and progression, a Cln8mnd mouse model was utilized to measure the impact and progression of histopathological and motor-behavioral outcomes between sexes. Immunohistochemistry staining utilized markers for intracellular storage materials, astrocytes, and microglial cells; sections were obtained of the thalamus and the somatosensory cortex of Cln8mnd mice.

Results: Several notable sex differences were observed in the presentation of brain pathology, including Cln8mnd female mice consistently presenting with greater GFAP+ astrocytosis and CD68+ microgliosis in the somatosensory cortex and ventral posteromedial/ventral posterolateral nuclei of the thalamus when compared to Cln8mnd male mice. Female Cln8mnd mice experienced a diminished lifespan by 0.5 months compared to their male counterparts (p less than 0.05). Furthermore, sex differences in motor-behavioral assessments identified Cln8mnd female mice experience poorer motor performance in the Morris Water Maze assessment, reverse Morris Water Maze, and increased tremors.

Conclusions: Female Cln8mnd mice perished earlier, performed worse on motor-behavioral assessments, and demonstrated marked microglial and astrocyte reactivity compared to their male counterparts. Taken together, the results provide further evidence of biological sex as a modifier of Batten disease progression and outcome, thus warranting consideration when conducting investigations and monitoring therapeutic impact.