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). Mitochondria show plasticity in morphology and function in response to neuronal activity, and previous research has reported impairments in mitochondrial morphology and function in disease. We and others have previously reported abnormalities in distinct types of homeostatic plasticity in FXS. It remains unknown if or how activity deprivation triggering 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 using a model of activity deprivation in cortical neurons from wild-type mice and that this plasticity-induced regulation is altered in Fmr1-knockout (KO) neurons. We uncovered dendrite-specific regulation of the mitochondrial surface area, whereas axon initial segment (AIS) mitochondria show changes in polarity; both responses are lost in the 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 could contribute to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.
Highlights
Mitochondria are essential for regulating cellular metabolism and maintaining neuronal health, and abnormal mitochondrial function is associated with altered neuronal development and disease (Valenti et al, 2014)
We utilize the same pharmacological approach to trigger homeostatic plasticity in Fmr1-KO and wild type (WT) cortical neurons to uncover how mitochondria are affected by activity chronic deprivation and the loss of FMR1
After 48 h of treatment, we performed immunocytochemistry to visualize the mitochondrial morphology in dendrites and the axon initial segment (AIS) using a primary antibody against the mitochondrial chaperone protein Hsp60 (Figure 1)
Summary
Mitochondria are essential for regulating cellular metabolism and maintaining neuronal health, and abnormal mitochondrial function is associated with altered neuronal development and disease (Valenti et al, 2014). HIP is critical for maintaining neuronal activity levels by regulating the intrinsic membrane excitability of neuronal membranes Another form of homeostatic plasticity is called synaptic scaling, which regulates neuronal activity by altering synaptic function. Dendrite-residing mitochondria become larger after activity silencing but become fragmented following increases in activity (Li et al, 2004; Chang and Reynolds, 2006) It remains unknown how mitochondrial shape/function is regulated at the molecular level during activity. We tested the hypothesis that activity perturbation triggers compartmentalized changes in the mitochondrion structure and function and that this mitochondrial plasticity is altered in Fmr1-KO neurons
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
