Activity-Dependent Mitochondrial Plasticity and Mitoproteome are Dysregulated in Fragile X Syndrome

Abstract

Homeostatic plasticity is necessary for the construction and maintenance of functional neuronal networks and becomes disrupted in certain neurodevelopmental disorders. Principal molecular mechanisms required for or modified by homeostatic plasticity are not well understood. We recently reported that homeostatic plasticity induced by activity deprivation is dysregulated in cortical neurons from Fragile X Mental Retardation protein (FMRP) knockout mice (Bulow et al. 2019). These findings suggested to us that proteins responsive to both activity deprivation and modulated by FMRP expression would be robust putative pathways necessary for or modified by homeostatic plasticity. Here, we used unbiased quantitative mass spectrometry to quantify steady-state proteome changes following chronic activity deprivation in wild type and Fmr1-/y cortical neurons. We found that most proteome hits responsive to both activity deprivation and the Fmr1-/y genotype were annotated to mitochondria. Surprisingly, we observed that Fmr1-/y neurons showed exaggerated changes in the expression of mitochondrial proteins following activity deprivation. We identified significant, but compartment specific, changes in the mitochondrial morphology and membrane polarization in dendrites and axons of wild type neurons following activity deprivation. However, these compartmentalized changes were already present in Fmr1-/y neurons at baseline and remained insensitive to activity deprivation. Our findings suggest that mitochondria are required and modified during the induction, establishment or maintenance of homeostatic plasticity. Loss of FMRP exaggerates changes in the mitoproteome during activity deprivation, but Fmr1-/y neurons fail to appropriately regulate mitochondrial morphology and function in an activity dependent and compartmentalized manner. We propose that abnormal compartmentalized mitochondrial plasticity contributes to neurodevelopmental disorders.