Autism is a neurobehavioraldisorder of unknown etiology that affects one in 68 children. We hypothesize that a major contributor to autismspectrum disorder (ASD) risk is partial mitochondrial dysfunction causing interneuron inhibition anddevelopmental migration defects. This results in cortical neuronal excitation-inhibition imbalance. Partialmitochondrial dysfunction has been repeatedly observed in ASD. ASD patients exhibit EEG abnormalities oflikely GABAergic inhibitory interneuron origin. Interneurons are highly energetic and acutely sensitive tomitochondrial inhibition and cortical excitation-inhibition imbalance is associated with ASD behavioralabnormalities. Extensive nuclear DNA (nDNA) genetic studies have identified multiple ASD-associatedhaploinsufficient loci, each accounting for a few cases, implying that there are over a thousand ASD loci. Themitochondrial genome consists of between one and two thousand nDNA genes plus thousands of copies of themitochondrial DNA (mtDNA), so partial mitochondrial dysfunction can result from nDNA haploinsufficiency ordeleterious mtDNA variants. We have shown that many ASD-associated nDNA haploinsufficiency variantsaffect mitochondrial functions, that certain mtDNA lineages (haplogroups) correlate with ASD-risk, that theASD-associated mtDNALeu(UUR) nt 3243A>G mutation results in mitochondrial dysfunction and perturbation ofexpression of multiple ASD nDNA genes, that chemical and genetic inhibition of OXPHOS impacts interneuroncortical developmental migration, and that mice harboring mild mtDNA mutants exhibit ASD-associatedendophenotypes including EEG abnormalities. To further test the mitochondrial defect-interneuron imbalancehypothesis we propose three specific aims. First, we will determine the mtDNA sequences of ASD patientsand controls using off-target exome sequence data or direct mtDNA sequencing and correlate the mtDNAhaplogroups and recent deleterious mutations with ASD risk. ASD-associated mtDNAs will then be analyzedfor mitochondrial dysfunction within transmitochondrial cybrids. Second, we will analyze 16p11.2 CNV ASDcell lines for mitochondrial dysfunction and altered transcription profiles and compare the results to ASDmtDNALeu(UUR) nt 3243A>G cybrids. We will then determine how mtDNA variation affects the clinical variabilityassociated with 16p11.2 CNVs. Finally, we will determine the effect of interneuron-specific nDNAmitochondrial gene and systemic mtDNA gene defects on cortical interneuron developmental migration andassociated manifestation of ASD endophenotypes and social-behavioral aberrations. Mice withendophenotypes but non-overt ASD-like behavior will be exposed to poly (I:C)-induced in utero inflammation todetermine if they are more prone to induction of ASD-like behavior. If validated by these experiments ourmitochondrial defect-interneuron imbalance hypothesis can encompass virtually all of the disparateobservations associated with ASD.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
