Role of Mitochondria in Variable Penetrance of Schizophrenia in 22q11.2 Deletion Syndrome via Influence on Presynaptic Mechanisms of Glutamate Release

About This Grant

PROJECT SUMMARY/ABSTRACT Schizophrenia (SZ) remains one of the most debilitating psychiatric disorders and mechanistic understanding of the disease is minimal. Glutamatergic neurotransmission may play a role in SZ, but this has been difficult to study directly as the developing brain is inaccessible and complicated psychiatric syndromes cannot be easily replicated in non-human animals. Work using neurons derived from patient stem cells (iNeurons) has demonstrated a way to circumvent these limitations, and data from Dr. Anderson’s lab suggest the variable penetrance SZ in a well-defined neurodevelopmental disorder (22q11.2 deletion syndrome; 22qDS) corresponds to impaired oxidative phosphorylation (OXPHOS) in mitochondria. This proposal addresses the fundamental question of how alterations in mitochondrial function lead to complex psychiatric symptoms of SZ. AIM1 will test the hypothesis that mitochondrial dysfunction in presynaptic compartments results in diminished glutamate release in iNeurons from 22qDS individuals with SZ (22q+SZ) relative to those without SZ [22q(-)SZ]. Optical imaging of glutamate (AIM1.1) and synaptic vesicle cycling (AIM1.2) will be used to assess glutamate release from individual nerve terminals by independent methods under both high and low frequency neuronal stimulation. AIM2 will use computational modeling to access how alterations in presynaptic mitochondrial function contribute to circuit connectivity and entropy (disorder) in (22q+SZ) and [22q(-)SZ] iNeurons. This proposal fits within NIMH’s Strategic Plan to define brain mechanisms underlying behavior and mental illness and is expected to generate insights into mitochondrial influence on presynaptic function and glutamatergic neurotransmission in the emergence of SZ symptoms in 22qDS while also establishing a robust model of human cellular, synaptic, and circuit neuropathology in patient derived cells. Dr. Rossano will receive training in induced pluripotent stem cell models, medium-to-high throughput synaptic imaging in patient-derived cells, computational modeling of circuit connectivity, and integration of mitochondrial biology with synaptic physiology. Drs. Anderson and Goldberg possess complementary expertise and are uniquely suited for this proposal. A thoughtfully selected advisory committee will provide further scientific and career mentorship. Together with the world-class resources available at the Children’s Hospital of Philadelphia and the University of Pennsylvania the proposed scientific and training objectives will allow Dr. Rossano to establish an independent research program focused on synaptic neuroscience and mitochondrial biology as therapeutically targetable mechanisms underlying symptoms in SZ, autism, and additional neurodevelopmental disorders.