Mitochondrial Dysfunction Leads to Cortical Under-Connectivity and Cognitive Impairment

Under-connectivity between cerebral cortical association areas may underlie cognitive deficits in neurodevelopmental disorders, including the 22q11.2 deletion syndrome (22q11DS). Using the LgDel 22q11DS mouse model, we assessed cellular, molecular, and developmental origins of under-connectivity and its consequences for cognitive function. Diminished 22q11 gene dosage reduces long-distance projections, limits axon and dendrite growth, and disrupts mitochondrial and synaptic integrity in layer 2/3 but not 5/6 projection neurons (PNs). Diminished dosage of Txnrd2, a 22q11 gene essential for reactive oxygen species catabolism in brain mitochondria, recapitulates these deficits in WT layer 2/3 PNs; Txnrd2 re-expression in LgDel layer 2/3 PNs rescues them. Anti-oxidants reverse LgDel- or Txnrd2-related layer 2/3 mitochondrial, circuit, and cognitive deficits. Accordingly, Txnrd2-mediated oxidative stress reduces layer 2/3 connectivity and impairs cognition in the context of 22q11 deletion. Anti-oxidant restoration of mitochondrial integrity, cortical connectivity, and cognitive behavior defines oxidative stress as a therapeutic target in neurodevelopmental disorders. [Display omitted] •Cortical connections decrease in a DiGeorge/22q11 deletion syndrome mouse model•Under-connectivity reflects reduced dendrite, axon, and synapse growth•Txrnd2, a 22q11 gene, regulates mitochondrial metabolism and neuron growth•Cortical connections and behavioral deficits are restored by anti-oxidant therapy Fernandez et al. use a mouse model of DiGeorge/22q11 deletion syndrome—a genetic neurodevelopmental disorder—to characterize biological mechanisms of neuronal under-connectivity, establish their role in higher-order behavior, and identify an effective pharmacological therapy.