Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

Abstract Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and Fragile X Syndrome (FXS). In parallel, recent studies have uncovered important basic functions of mitochondria to power protein synthesis, synaptic plasticity and neuronal maturation. The mitochondrion also responds to neuronal activity by altering its morphology and function, and this plasticity of the mitochondrion appear important for proper neuronal plasticity. Previous research has reported disease induced changes in mitochondrial morphology and function, but it remains unknown how such abnormalities affect the ability of mitochondria to express activity dependent plasticity. This study addresses this gap in knowledge using a mouse model of FXS. We previously reported abnormalities in one type of homeostatic plasticity, called homeostatic intrinsic plasticity, which is known to involve structural changes in the axon initial segment (AIS). Another form of homeostatic plasticity, called synaptic scaling, which involves postsynaptic changes in dendrites, is also impaired in FXS. It remains unknown if or how homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment specific manner during homeostatic plasticity in cortical neurons from wild type mice, and that this plasticity-induced regulation is altered in Fmr1 KO neurons, as a model of FXS. We uncovered dendritic specific regulation of mitochondrial surface area, whereas AIS mitochondria show changes in polarity; both responses are lost in Fmr1 KO. Taken together our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS contributes to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.