Several lines of evidence link the endogenous neuromodulator kynurenic acid (KYNA), a major metabolite of the essential amino acid tryptophan and antagonist of both a7 nicotinic and N-methyl-D-aspartate (NMDA) receptors, causally to the cognitive deficits seen in individuals with schizophrenia (SZ): 1) brain and cerebrospinal fluid KYNA levels are increased in SZ; 2) a7 nicotinic and NMDA receptors play critical roles in both neurodevelopment and cognition; 3) in animals, perinatal increases in brain KYNA cause an array of SZ-like abnormalities and vulnerabilities in adulthood; 4) experimental KYNA elevations cause cognitive dysfunctions reminiscent of SZ; 5) brain KYNA metabolism is stimulated by stress and immune stimulation during early development; and 6) first results indicate that inhibitors of KYNA biosynthesis (KAT II inhibitors) show efficacy in animal preparations that are believed to be informative for SZ pathophysiology. The proposed Center is based on three premises: 1) SZ is a complex psychiatric illness in which stress/immune challenges during pregnancy set the stage for the emergence of the disease in vulnerable offspring; 2) Stressful events during development precipitate the early presentation of cognitive impairments in susceptible individuals by disproportionally elevating brain KYNA levels; and 3) Pharmacological reduction of brain KYNA synthesis offers a promising new therapeutic target in SZ, especially for pro-cognitive interventions. Hypotheses derived from these insights and from supportive preliminary results in animals and humans will be tested in two pre-clinical and two clinical projects. All studies will be led by established and highly interactive laboratory-based and clinical faculty, and the host institution has the appropriate infrastructure to embark on this overarching and highly synergistic translational project. Notably, the planned research strategy fits the Strategic Plan of the NIMH, which calls for a) discoveries of the causes of mental disorders, b) charting of disease trajectories to optimize treatment, and c) the development of new and better therapeutic interventions.

Public Health Relevance

Deficits in cognitive functions are a core symptom of pathology in schizophrenia, a debilitating disorder affecting ~ 1 % of the world population. The proposed Center, organized in four highly complementary and synergistic projects in animals and humans, is designed to provide new insights into the role of the tryptophan metabolite kynurenic acid (KYNA) in cognition, and to examine inhibition of KYNA formation as a novel strategy to overcome cognitive impairments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH103222-05
Application #
9442823
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Meinecke, Douglas L
Project Start
2014-05-09
Project End
2019-02-28
Budget Start
2018-03-27
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Psychiatry
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Ryan, Meghann C; Kochunov, Peter; Sherman, Paul M et al. (2018) Miniature pig magnetic resonance spectroscopy model of normal adolescent brain development. J Neurosci Methods 308:173-182
Chiappelli, Joshua; Rowland, Laura M; Notarangelo, Francesca M et al. (2018) Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia. Neuropsychopharmacology 43:1706-1711
Secci, Maria E; Mascia, Paola; Sagheddu, Claudia et al. (2018) Astrocytic Mechanisms Involving Kynurenic Acid Control ?9-Tetrahydrocannabinol-Induced Increases in Glutamate Release in Brain Reward-Processing Areas. Mol Neurobiol :
Savransky, Anya; Chiappelli, Joshua; Fisseha, Feven et al. (2018) Elevated allostatic load early in the course of schizophrenia. Transl Psychiatry 8:246
Clark, Sarah M; Vaughn, Chloe N; Soroka, Jennifer A et al. (2018) Neonatal adoptive transfer of lymphocytes rescues social behaviour during adolescence in immune-deficient mice. Eur J Neurosci 47:968-978
Albrecht, Matthew A; Vaughn, Chloe N; Erickson, Molly A et al. (2018) Time and frequency dependent changes in resting state EEG functional connectivity following lipopolysaccharide challenge in rats. PLoS One 13:e0206985
Du, Xiaoming; Hong, L Elliot (2018) Test-retest reliability of short-interval intracortical inhibition and intracortical facilitation in patients with schizophrenia. Psychiatry Res 267:575-581
Du, Xiaoming; Rowland, Laura M; Summerfelt, Ann et al. (2018) TMS evoked N100 reflects local GABA and glutamate balance. Brain Stimul 11:1071-1079
Du, Xiaoming; Rowland, Laura M; Summerfelt, Ann et al. (2018) Cerebellar-Stimulation Evoked Prefrontal Electrical Synchrony Is Modulated by GABA. Cerebellum :
Song, Chang; Clark, Sarah M; Vaughn, Chloe N et al. (2018) Quantitative Analysis of Kynurenine Aminotransferase II in the Adult Rat Brain Reveals High Expression in Proliferative Zones and Corpus Callosum. Neuroscience 369:1-14

Showing the most recent 10 out of 78 publications