Neurobiology of MIF in development and disease

Emory University, Atlanta GA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Macrophage migration inhibitory factor (MIF) is a unique molecule that functions as a cytokine and a hormone, and is induced by infections and psychological stress in animal models. Moreover, MIF is highly abundant in the brain and appears to have enzymatic activity that may participate in dopamine metabolism. MIF is encoded by a single gene on human chromosome 22q11.2, and its amino acid sequence has minimal homology with other identified biological response modifiers in mammals. There is little data concerning the function of MIF in the brain, and there is a lack of information as to whether MIF is involved in neurological or psychiatric disorders. MIF amplifies proinflammatory cytokine production by interfering with the immunosuppressive properties of endogenous glucocorticoids. This effect of MIF during neurodevelopment has not been well studied. A confluence of data from other laboratories supports the idea that proinflammatory cytokines may constitute a common pathway for prenatal or perinatal brain injury due to diverse insults in humans. Thus, in Aim 1 we will use transgenic mice to investigate the role of MIF in maternal/fetal inflammatory responses and neurodevelopmental outcomes. These studies may provide clues to schizophrenia, which has been linked to chromosome 22q11-12, and is associated with aberrant neurodevelopment due to prenatal or perinatal obstetric complications. We will also test the offspring of dams treated with inducers of MIF for changes in prepulse inhibition (PPI) and alterations in hippocampal volume as adults. Likewise, the idea that MIF is involved in dopaminergic neurotransmission warrants further study. This will be explored in Aim 2. We will tests the idea that mice lacking MIF (knockout mice) will have a reduced number of dopamine neurons and abnormal catecholamine metabolism. In addition, we will determine whether the dopamine antagonist, haloperidol, can influence blood levels of MIF. In AIM 2, we also plan to examine the relationship between MIF and the peptide, angiotensin II. Studies by other investigators have shown that this peptide can be made locally in the brain and is capable of inducing MIF. It has also been shown that angiotensin II promotes dopamine neurotransmission, and therefore we will determine whether this action is dependent on MIF. Besides schizophrenia, these studies could provide insight into Parkinson's disease, and maternal mental illnesses. [unreadable] [unreadable] [unreadable]