Schizophrenia is a debilitating disease of major public health importance. Although the causes of schizophrenia are not known, a role for hyperactivity of the dopamine system in the positive symptoms associated with schizophrenia has long been inferred from the antipsychotic response to D2 dopamine receptor antagonists and because the dopamine releaser amphetamine can be psychotogenic. Recent imaging studies suggest enhanced amphetamine induced dopamine release in schizophrenia patients but the underlying mechanisms are unknown, in part due to the lack of an animal model. Individuals with 22q11.2 microdeletion have cognitive deficits and a high risk of developing schizophrenia. A mouse model carrying a 1.3-Mb chromosomal deletion, Df(16)A mice, that is synthetic to the human 22q11.2 1.5-Mb microdeletion shows features that parallel schizophrenia. Our preliminary data indicate that there is an altered dopamine release in acutely derived corticostriatal slices. We hypothesize that dopamine dysregulation in schizophrenia is in part due to intrinsic changes in the presynaptic dopamine terminals. To test this hypothesis, we propose to characterize dopamine storage, release, and plasticity in this mouse model both in the striatum and prefrontal cortex. We will employ fast-scan cyclic voltammetry and a novel optical imaging approach which enables to visualize dopamine storage and release at individual terminals to elucidate the mechanisms that may underlie the aberrant dopamine release in schizophrenia. In particular, we plan to determine whether dopamine transporters and/or the synaptic vesicle pH have been altered in the mutants. These studies will reveal the mechanisms underlying the dysregulation of dopamine neurotransmission and may offer insights into the development of new approaches for the treatment of schizophrenia.
We propose to characterize dopamine release in a mouse model of schizophrenia, the 22q11.2 microdeletion mice, to test the hypothesis that dopamine dysregulation in schizophrenia in part results from intrinsic changes in the presynaptic dopamine terminals.
|Rodriguez, Pamela C; Pereira, Daniela B; Borgkvist, Anders et al. (2013) Fluorescent dopamine tracer resolves individual dopaminergic synapses and their activity in the brain. Proc Natl Acad Sci U S A 110:870-5|