PROJECT SUMMARY
Microglia are immunocompetent cells that interact dynamically with multiple cell types to shape brain
development and maintain neural circuits. It has been hypothesized that dysfunction of microglia may
contribute to the development and clinical course of schizophrenia (SZ). However, recent evidence has shifted
our understanding from a model that involved neuroinflammatory microglial response. Instead, evidence
supports a SZ model whereby microglia show dysfunction that disrupts neuroplasticity, neurocircuit
development, and neurotransmission, ultimately altering glutamatergic and dopaminergic signaling along
relevant frontostriatal circuits and onset of psychosis in late adolescence or adulthood. Molecular imaging
agents for clinical and translational study of microglia in the brains of diseased populations or model systems,
including SZ, are eagerly pursued. In this proposal we focus on the colony stimulating factor 1 receptor
(CSF1R), which is an imaging target expressed on the cell surface of microglia. CSF1R is an attractive imaging
target because it is chiefly expressed by microglia, and not other cell types in brain parenchyma. Toward
measuring CSF1R in vivo, we developed [11C]CPPC (CPPC), a PET radiotracer that has optimized properties
for neuroimaging. This project also builds on our previous studies of microglia in early stages of psychosis, and
recent published evidence supporting low CSF1R in brain tissue of patients with SZ. Based on published
evidence and preliminary data, we hypothesize lower CSF1R, consistent with downregulation of this microglial
marker, in the striatum and in dorsolateral prefrontal cortex (DLPFC) of individuals with recent onset of SZ
compared to healthy controls. Within SZ, we hypothesize that lower CSF1R in striatum will be associated with
amotivation. Lower CPPC binding in DLPFC will be associated with impaired cognitive control and lower
working memory performance. Study of the relationship between microglial marker signatures and clinical
sequelae in SZ in the intact human brain is ideal since these cells change their phenotype outside this natural
milieu. Our study may position CPPC PET as a promising tool for human and back-translational research
aimed at studying, monitoring, or reprogramming the microglial response in SZ or related animal models.