Chaperone-mediated autophagy sex-specifically regulates neuronal activity by remodeling the synaptic proteome

Chaperone-mediated autophagy (CMA) declines in aging and neurodegenerative diseases. CMA loss in neurons leads to neurodegeneration and behavioral changes in mice, but the role of CMA in neuronal physiology is largely unknown. Here, we show that CMA deficiency causes neuronal hyperactivity, disrupted calcium homeostasis and abnormally increased presynaptic neurotransmitter release in females and elevated postsynaptic AMPA signaling in males. Comparative quantitative proteomics revealed sexual dimorphism in the synaptic proteins degraded by CMA, with preferential remodeling of the presynaptic proteome in females and the postsynaptic proteome in males. We propose that impaired lysosomal degradation of these synaptic proteins may contribute to hyperexcitability in aging and neurodegeneration. Accordingly, we demonstrate that pharmacological CMA activation in an Alzheimer’s disease mouse model normalizes synaptic protein levels and neurotransmission. These findings unveil a role for CMA in the regulation of neuronal excitability and highlight this pathway as a potential target for mitigating age-related decline in neuronal function.