Neurodevelopmental Deficits in 22q11.2 Deletion Syndrome: The Potential of Mitochondria as Novel Pharmacological Targets

Background: 22q11 deletion syndrome (22q11DS), also referred to as DiGeorge syndrome, is a severe neuropsychiatric disorder characterized by an abnormal development of cortical neurons. Children with this condition typically present grave cognitive deficits and are at high risk of developing psychosis later in life. It is caused by a hemizygous 1.5-3 Mb microdeletion on the long arm of chromosome 22. This alteration affects approximately 35 to 60 known genes, among which six (Prodh, Slc25al, Mrpl40, Zdhhc8, T10 and Txnrd2) encode for mitochondrial proteins. This was found to have a strong influence on the pathology, as recent studies have revealed mitochondrial dysfunctions in both patients and mice models of the disease. One of the brain areas most affected by these abnormalities is the Prefrontal Cortex (PFC), already well-known for its association with schizophrenia and executive functions deficits. Methods and results: In this study, we took advantage of the LgDel mouse model (i.e., a mouse model of 22q11DS) to analyse mitochondrial genes expression during development and we found a persistent downregulation of Bcl2 and Bcl-xL (anti-apoptotic proteins that contribute to neuronal function). The BH4 domain of Bcl-xL is known to contribute to a variety of cell functions, including mitochondrial biogenesis and mitodynamics. Therefore, we decided to exploit a pharmacological agent, the TAT-BH4 peptide, to re-express the BH4 domain in vivo during development. The treatment was able to rescue the LgDel cognitive impairments, proving the presence of an underlying change in the mice’s neural network. Thus, we investigated the molecular mechanism enabling the phenotypic rescue and we proved that TAT-BH4 acts on L5 pyramidal neurons restoring normal mitochondrial morphology, basal dendrites length, synaptic integrity and neural circuit function. Conclusions: Therefore, cognitive deficits and psychosis in LgDel mice are strictly related to mitochondrial dysfunctions in the PFC, and can be prevented by the administration of TAT-BH4 during a sensitive time window in late childhood/early adolescence. These findings suggest that in the future similar therapeutic strategies could be used to prevent the emergence of schizophrenia and other severe psychiatric disorders in DiGeorge syndrome patients. Interestingly, the following steps of this research will be aimed at investigating natural compounds with anti-oxidant properties that could replace the TAT-BH4 peptide. This would allow a much higher compliance in terms of administration, whilst safeguarding the beneficial effects on mitochondria.