A significant body of research supports the idea that deficits in cortical fast-spiking inhibitory systems may underlie the psychotic features and cognitive deficits associated with schizophrenia-related disorders. Recent data from neurodevelopmental animal models indicate that the loss of function of the parvalbumin-(PV) positive fast-spiking inhibitory neurons may occur early during postnatal development, specifically during the critical period of their maturation. These results strongly suggest that the period of active maturation of this fundamental inhibitory system may constitute a sensitive period during which the confluence of genetic and environmental factors may set the stage for the development of schizophrenia-like symptoms in late adolescence/early adulthood. Thus, studies directed to determine factors that affect the maturational process of this inhibitory system may shed light into the origins of schizophrenia. This project will test two primary hypotheses: (1) that the period of maturation of PV-interneuronal circuits constitutes a sensitive period in which increased oxidative stress in brain, due to the activation of the IL-6/Nox2 pathway, leads to schizophrenia-like behavior in early adulthood;and (2) that this sensitive period also constitutes a "window of intervention" for pharmacological treatment strategies aimed at prevention of psychosis. These hypotheses will be tested in mice subjected to two developmental manipulations known to lead to disruptions in the PV- interneuronal circuitry and schizophrenia-related behaviors in early adulthood: i.e. perinatal exposure to the NMDA receptor antagonist ketamine (pNM model), and social isolation rearing (SI model).
Three specific aims will be developed:
Aim 1 will test the hypothesis that there is a sensitive period of brain redox dysregulation in the pNM and SI models that leads to schizophrenia-like neurochemical and behavioral disruptions in late adolescence/early adulthood.
Aim 2 will determine whether increased brain and circulating IL-6 correlate with active oxidative stress in brain in the two developmental models, assess whether circulating IL-6 constitutes a peripheral biomarker predictive of brain dysfunction, and test whether the neurochemical and behavioral effects of SI and pNM are absent in IL-6 KO mice. And finally, Aim 3 will assess whether early or late interventions leading to attenuation of brain oxidative stress, by use of a Nox2 inhibitor (apocynin), an IL-6 blocker, or by increasing antioxidant defenses with N-acetyl cysteine, protects the PV-interneuronal system and prevents development of schizophrenia-like behaviors in late adolescence/early adulthood. Public Health Impact: This project studies a specific set of inhibitory neurons which are critical for normal cognitive function, and known to be dysfunctional in schizophrenia. The proposed studies may suggest novel anti-inflammatory and/or anti-oxidant treatments during early life to protect this fundamental GABAergic system and thus prevent the development of schizophrenia and other psychotic conditions.

Public Health Relevance

Schizophrenia affects millions of Americans when they reach early adulthood, but to date, there is scarce knowledge of the underlying disease processes occurring before symptoms appear. Using two neurodevelopmental mouse models of schizophrenia, this project will determine whether the period of maturation of inhibitory circuits, during early postnatal development, constitutes a sensitive period when the brain is most vulnerable to oxidative stress processes that lead to the dysfunction of specific inhibitory circuits and the appearance of schizophrenia-like symptoms in early adulthood. These studies will delineate the mechanisms inducing the increased oxidative stress in two models and the periods when they occur, and assess whether strategies that prevent oxidative stress ameliorate the neurochemical and behavioral disruptions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH091407-03
Application #
8269120
Study Section
Special Emphasis Panel (ZMH1-ERB-L (02))
Program Officer
Desmond, Nancy L
Project Start
2010-07-19
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$426,938
Indirect Cost
$111,994
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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