ABSTRACT
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.
Subject(s)
Cerebral Cortex/metabolism , Cognitive Dysfunction/genetics , DiGeorge Syndrome/genetics , Mitochondria/metabolism , Neurons/metabolism , Reactive Oxygen Species/metabolism , Thioredoxin Reductase 2/genetics , Animals , Axons/ultrastructure , Behavior, Animal , Cerebral Cortex/cytology , Dendrites/ultrastructure , Disease Models, Animal , Entorhinal Cortex/metabolism , Frontal Lobe/metabolism , Gene Dosage , Mice , Mitochondria/ultrastructure , Neural Pathways , Neurons/ultrastructure , Synapses/metabolism , Synapses/ultrastructureABSTRACT
BTBR T+tf/J (BTBR) inbred mice are frequently used as a model of autism spectrum disorders (ASD) as they display social deficits and repetitive behaviors that resemble the symptoms of the human syndrome. Since deficits on tasks that measure cognitive (executive) control are also reliable phenotypes in ASD, we wanted to determine whether executive abilities were compromised in the mouse model. BTBR mice were trained on two visual discrimination paradigms requiring differing degrees of cognitive control. BTBR mice performed normally on a visual discrimination reversal where rule switching was relatively automatic, but were severely impaired on a task-switch paradigm that required the active use of contextual information to switch between rules in a flexible manner. The present findings further characterize the behavior of BTBR mice as a model of ASD. Moreover, the demonstration of both intact and impaired executive functions in BTBR mice illustrates the importance of developing new cognitive assays for comprehensive behavioral assessment of mouse models of human brain disorders.