The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion of a segment on the 22nd
chromosome. This syndrome affects several organ systems, including the brain, with substantial
neurocognitive and neuropsychiatric implications. About a third of early adolescents to young adults
are diagnosed with schizophrenia or schizophrenic-like disorders. It motivated neuroscientists and
psychiatrists to use this disease as a model to understand better the neurobiological mechanisms
underlying schizophrenia. The 22q11.2 deletion syndrome encompasses a 1.5 or 3.0 megabase
(Mb) segment with up to 60 genes, 6 encoding mitochondrial proteins. The role of mitochondria in
patients and mice models of 22q11.2DS and schizophrenia is currently explored to unravel neuronal
pathological features. These anomalies are well described within the prefrontal cortex (PFC), which
plays an essential role in cognition and psychiatric conditions such as schizophrenia.
In this study, we used a mouse model of 22q11.2DS and observed a reduction in the expression of
two genes, Bcl-2 and Bcl-xL. Both genes are involved in anti-apoptosis mechanisms and neuronal
functions. The two proteins encoded by these genes share a BH4 domain with various functions,
including mitochondrial biogenesis and neuronal development. This domain was then exploited to
create a pharmacological peptide, TAT-BH4, to interact with its targets during in vivo brain
development, focusing on the PFC neurons in layers 5 and 2/3. We found that this pharmacological
approach restored mitochondrial morphology and two behavioural features: working memory and
normal locomotor activity. However, the treatment did not show any effect on the self-grooming
behaviour.
This pharmacological approach re-enforces the concept that 22q11.2DS and schizophrenia share a
mitochondrial aetiology that can be specifically targeted in a developmental time window to restore
normal cellular and behavioural features.