Resting state fMRI detects pathological functional brain connectivity in the Ndufs4 knockout mouse model of Leigh syndrome during the pre-symptomatic stage of the disease

Abstract

Leigh syndrome (LS) is a progressive encephalopathy and generally regarded as the most common inborn mitochondrial disease. Mutations in mitochondrial respiratory complex I are common in patients with LS and a mutational hotspot has been identified in the gene that encodes the NDUFS4 subunit of respiratory complex I. The Ndufs4 knockout mouse (Ndufs4 KO) model of LS closely resembles the phenotypes of LS patients and show like the patient brain lesions when the symptoms are manifested. It is speculated but unproven that brain functional connectivity may precede the onset of symptoms. Therefore, the present study was set out to investigate the progression of brain functional connectives in Ndufs4 KO mice before and after the manifestation of LS-like symptoms using in vivo resting-state functional magnetic resonance imaging (rs-fMRI). Since the brain lesions may be caused by increased reactive oxygen species (ROS) in the brain, we also examined the potential protective effect of KH176, a small molecular for modulating ROS levels, on brain functional connectivity. Rs-fMRI results showed that in Ndufs4 KO mice the functional connectivity of the piriform cortex, motor cortex, barrel cortex, visual cortex, auditory cortex, prefrontal cortex, lateral striatum, ventral striatum cortex and amygdala was increased, starting from the pre-symptomatic stage (middle stage) to the symptomatic stage (late stage) of the disease. KH176 had no effect on the changes in functional connectivity in the mice. In conclusion, these results show that there are abnormalities in functional connectivity in Ndufs4 KO mice during the pre-symptomatic phase of the disease and that KH176 treatment does not modify the connectivity changes.