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.

Public Health Relevance

This project continues to address the 'adenosine hypothesis of schizophrenia', which implies that dysregulation of the brain's endogenous homeostatic network regulator adenosine affects a wide spectrum of symptomatology relevant to schizophrenia. Here we will focus on neurodevelopmental mechanisms, which might interfere with adenosine homeostasis as a possible explanation for the genesis of schizophrenia-related behavior in mice. In carefully selected behavioral tests we will assess whether adenosine-based modulation of neurodevelopmental or glial mechanisms can prevent the development or the expression of schizophrenia- related behavior, respectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH083973-06A1
Application #
8760708
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Winsky, Lois M
Project Start
2008-07-01
Project End
2016-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
$412,500
Indirect Cost
$162,500
Name
Emanuel Hospital and Health Center
Department
Type
DUNS #
050973098
City
Portland
State
OR
Country
United States
Zip Code
97232
Köhler, David; Streienberger, Ariane; Morote-García, Julio C et al. (2016) Inhibition of Adenosine Kinase Attenuates Acute Lung Injury. Crit Care Med 44:e181-9
Sandau, Ursula S; Colino-Oliveira, Mariana; Jones, Abbie et al. (2016) Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity. J Neurosci 36:12117-12128
Boison, Detlev (2016) The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine. Front Mol Neurosci 9:26
Boison, Detlev (2016) Adenosinergic signaling in epilepsy. Neuropharmacology 104:131-9
Toti, Kiran S; Osborne, Danielle; Ciancetta, Antonella et al. (2016) South (S)- and North (N)-Methanocarba-7-Deazaadenosine Analogues as Inhibitors of Human Adenosine Kinase. J Med Chem 59:6860-77
Acharya, Munjal M; Baulch, Janet E; Lusardi, Theresa A et al. (2016) Adenosine Kinase Inhibition Protects against Cranial Radiation-Induced Cognitive Dysfunction. Front Mol Neurosci 9:42
Boison, Detlev; Aronica, Eleonora (2015) Comorbidities in Neurology: Is adenosine the common link? Neuropharmacology 97:18-34
Matos, Marco; Shen, Hai-Ying; Augusto, Elisabete et al. (2015) Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia. Biol Psychiatry 78:763-74
Dubroqua, Sylvain; Low, Samuel R L; Yee, Benjamin K et al. (2015) Caffeine impairs the acquisition and retention, but not the consolidation of Pavlovian conditioned freezing in mice. Psychopharmacology (Berl) 232:721-31
Dubroqua, Sylvain; Singer, Philipp; Yee, Benjamin K (2014) Deletion of forebrain glycine transporter 1 enhances conditioned freezing to a reliable, but not an ambiguous, cue for threat in a conditioned freezing paradigm. Behav Brain Res 273:1-7

Showing the most recent 10 out of 47 publications