Adenosine and schizophrenia: mechanisms and therapies

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DESCRIPTION (provided by applicant): This renewal application continues to address the 'adenosine hypothesis of schizophrenia', which predicts that disruption of adenosine (ADO) homeostasis in the brain produces behavioral effects mimicking specific schizophrenia (SZ) symptoms. Studies from our previous funding period demonstrated that disruption of ADO homeostasis in the adult brain affected multiple brain circuits implicated in the pathophysiology of SZ. Importantly, we provided evidence for the antipsychotic potential of ADO augmentation therapy. Our renewal application will assess the contribution of developmental dysfunction of ADO homeostasis to the genesis of SZ-related symptoms in mice. Our proposed work is based on the following rationale: (i) ADO regulation plays a critical role in brain development. (ii) The placental ADO-barrier plays a key role in separating the maternal from the fetal ADO-system. (iii) Prenatal immune stimulation, an environmental risk factor for SZ, challenges developmental ADO homeostasis. (iv) ADO homeostasis in the adult brain is under the control of astrocytes; therefore impairment of astrocyte physiology will affect ADO homeostasis. (v) Data from our previous funding period demonstrated an anti-SZ potential of therapeutic ADO augmentation. Here, we will address the CENTRAL HYPOTHESIS that developmental dysfunction of adenosine homeostasis contributes to the pathophysiology of schizophrenia; and that adenosine-based interventions provide new opportunities for therapeutic interventions. Using a novel set of transgenic mice with conditional mutations affecting ADO-homeostasis during fetal brain development, ADO-based therapeutic manipulations at the maternal/fetal interface in the mouse gestational infection model of SZ, ADO-based therapeutic interventions during adolescence and adulthood, and behavioral assays to tax selected SZ-related behavioral traits, we will address our hypothesis in three Specific Aims: (1) Test the hypothesis that fetal disruption of ADO homeostasis affects brain development. (2) Test the hypothesis that dysregulation of ADO homeostasis contributes to the neurodevelopmental derailments implicated in the gestational infection model of SZ. (3) Test the prediction that postnatal ADO augmenting interventions can prevent or suppress SZ-related symptoms in offspring derived from a prenatal immune challenge. Significance and Impact: The proposed project will define the role(s) of specific adenosinergic dysfunctions during fetal brain development as possible precipitating factor for the development of SZ. Importantly, our research will test preventative therapeutic measures directly interfering with ADO signaling at the maternal/fetal inter- face. In addition our findings will address a critical gap in knowledge about the potential link between ADO, brain development, glia, and SZ - a much understudied research field. By identifying the therapeutic potential of restoring astrocyte-based ADO-dependent homeostatic control of brain functions in adolescence and adult- hood, our studies will define a novel therapeutic principle for the prevention and treatment of SZ.