The 22q11.2 microdeletion syndrome (22q11.2 DS), is associated with ~20-fold increased risk for psychosis.
Brain imaging studies have consistently demonstrated abnormal functional connectivity in the cerebral cortex.
Preclinical studies using cerebral cortex neurons derived from human induced pluripotent stem cells (hiPSC),
revealed mitochondrial defects, neuronal hyperexcitability and calcium signaling defects, supporting the findings
of cortical circuit dysfunction. However, the exact cellular and molecular mechanisms by which the 22q11.2
deletion leads to abnormal development and function of the cerebral cortex remain to be elucidated.
The 22q11.2 chromosomal region contains 9 genes associated with mitochondrial energy production. Human
blood samples revealed increased glycolysis, suggesting global metabolic alterations. Despite growing evidence
for mitochondrial and neuronal dysfunction in 22q11.2 DS, the metabolic and mitochondrial dysregulations
present in the human developing cerebral cortex remain unknown.
We will test the hypothesis that human mitochondrial defects begin in proliferating neural progenitors and
impair temporal mitochondrial maturation, induce metabolic reprogramming and subsequent neuronal function
defects. We hypothesize these metabolic abnormalities are less pronounced in rodent models of disease.
Aim 1 will identify mitochondrial defects during cortical development in hCS and forebrain sections from a mouse
model for 22q11.2 DS, using advanced microscopy and functional assays.
Aim 2 will assess for metabolic alterations during cortical development in hCS and forebrain sections from a
mouse model for 22q11.2 DS, using untargeted metabolomics and cell type-specific metabolic profile.
Aim 3 will identify metabolic pathways as targets for therapeutic interventions by testing the rescue potential of
drugs known to enhance mitochondrial function (e.g. nicotinamide riboside, resveratrol, bezafibrate).
Our multidisciplinary project will identify the initial timing and the exact metabolic and mitochondrial alteration
during the development of the cerebral cortex in 22q11.2 DS and pinpoint metabolic pathways for drug discovery,
(ii) assess for interspecies differences, and (iii) establish in vitro human neurometabolomics assays to study
other metabolic disorders of genetic or environmental etiology.