SUBSIDIOS PEW / FUNDACIÓN BUNGE Y BORN / FUNDACIÓN WILLIAMS
Dissecting altered dopaminergic neural pathways in Schizophrenia
Instituto Multidisciplinario de Biología Celular
Schizophrenia (SZ) has long been associated with alterations in dopamine (DA) neurotransmission1. Abnormalities in the DA system have been implicated in the alterations in reward processing and the deficits in reinforcement learning that are observed in patients with SZ (SZ patients). There are several DA projection pathways in the brain and in SZ the most well replicated finding of DA dysfunction has been an excess of DA release specifically in the associative striatum2,3. In contrast to this excess, a reduction in DA release in the prefrontal cortex (PFC) has been postulated, but until recently, never directly measured. A new study has for the first time documented a reduction in DA release in the PFC, and surprisingly this PET imaging study also revealed a widespread reduction in DA release extending to many cortical and extra-striatal regions4. The relationship between these opposing changes in DA release in patients is unknown, but translational studies have shown that alteration of dopaminergic activity in one region can induce changes others2. For example, studies in transgenic mice with developmental overexpression of striatal DA D2 receptors (D2R) suggest that increased DA D2R signaling can lead to irreversible cortical DA and cognitive dysfunction2,5. This implies that changes produced specifically in the striatum can have an effect in the functionality of the cortex. The reverse could also occur; changes in the cortex may induce changes in the striatum. Understanding how DA release pathways could be altered in opposite directions would provide an increase in our understanding of the etiology of the disease and also suggest targets for improved drug development. Prodromal studies show that striatal dopaminergic excess occurs before the onset of frank psychosis, suggesting that it is an early marker in the disease6-8. Due to the limitation of tools for studying the development of DA dysfunction in patients, one must use models to question the temporal and causal relationships between these changes and also which changes induce specific symptoms. Using fast scan cyclic voltammetry (FSCV)9, I can monitor in vivo DA release in mice where changes in select dopaminergic pathways have been induced. In order to dissect the differential effects of altered DA neural pathways, I propose to model two of the DA alterations observed in SZ in transgenic mice. This will allow me to study their unique contribution to the different symptoms. First, I propose to model the increase of DA activity observed in the associative striatum of SZ patients by increasing DA synthesis and release from the neurons that selectively project to this region. Second, I propose to model the decrease of DA release observed in the prefrontal cortex (PFC) of SZ patients by reducing burst firing in midbrain DA neurons that project to this region. In both models, I will study the mice in a battery of tests to determine how cognition and motivation are affected. I will also use FSCV to measure DA release in the areas that have been targeted in each model as well as other non-targeted regions. This will allow me to determine the possible etiological steps in DA dysregulation in SZ.