PTEN deficiency in postnatally developing Purkinje cells disrupts metabolic signaling, leading to dendritic abnormalities and sex-specific behavioral deficits

Abstract

Abstract Conditional deletion of the Pten gene in cerebellar Purkinje cells (PCs) results in cellular hypertrophy, neurodegeneration, and autism-like behaviors in adult mice. Here, we investigated the effects of PTEN conditional deficiency on PC dendritic development and early postnatal motor, spontaneous, and social behaviors. We found that Pten loss disrupts dendritic growth by altering mTOR signaling and reducing AMPK phosphorylation, leading to early motor deficits and sex-specific behavioral alterations. In vivo analysis revealed significant reductions in mitochondrial and lysosomal volume in developing dendrites. Notably, ex vivo treatment with AICAR (an AMPK activator) or Torin1 (an mTOR inhibitor) partially restored dendritic organelle content in Pten-deficient PCs. These findings suggest that PTEN is critical for maintaining metabolic balance during postnatal dendritic maturation, and its loss leads to structural and functional impairments in PCs that contribute to behavioral phenotypes in a sex- and age-dependent manner.

Keywords

• PTEN
• Purkinje cells
• mTORC1
• Mitochondria
• Lysosomes
• AMPK