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Mitochondrial Dysfunction Leads to Cortical Under-Connectivity and Cognitive Impairment.
Alejandra Fernandez1, Daniel W Meechan2, Beverly A Karpinski2
1GW Institute for Neuroscience, The George Washington University, Washington, DC 20037, USA; Department of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20037, USA; GW Institute for Biomedical Sciences, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
Neuron
|May 14, 2019
Summary
Cognitive deficits in 22q11.2 deletion syndrome (22q11DS) stem from reduced brain connectivity. Antioxidants targeting oxidative stress can restore mitochondrial function, neural connections, and cognitive behavior in this neurodevelopmental disorder.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Under-connectivity in the brain's association areas is linked to cognitive impairments in neurodevelopmental disorders like 22q11.2 deletion syndrome (22q11DS).
- Understanding the cellular and molecular origins of this under-connectivity is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the cellular, molecular, and developmental causes of under-connectivity in the LgDel 22q11DS mouse model.
- To determine the consequences of this under-connectivity for cognitive function.
- To explore the role of Txnrd2 and oxidative stress in these deficits and their potential as therapeutic targets.
Main Methods:
- Utilized the LgDel 22q11DS mouse model to study neurodevelopmental deficits.
- Assessed gene dosage effects on neuronal projections, axon/dendrite growth, and mitochondrial/synaptic integrity.
- Investigated the function of Txnrd2 and the impact of oxidative stress using genetic manipulation and antioxidant treatments.
Main Results:
- Reduced 22q11 gene dosage led to diminished long-distance projections and impaired growth in layer 2/3 projection neurons.
- Diminished Txnrd2 levels caused mitochondrial dysfunction, reduced connectivity, and cognitive deficits, which were reversible with Txnrd2 re-expression.
- Antioxidant treatment ameliorated mitochondrial, circuit, and cognitive deficits in both the LgDel model and Txnrd2-deficient neurons.
Conclusions:
- Oxidative stress, mediated by Txnrd2 dysfunction, is a key contributor to under-connectivity and cognitive deficits in 22q11DS.
- Restoring mitochondrial integrity and cortical connectivity through antioxidant intervention offers a promising therapeutic strategy for neurodevelopmental disorders.
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