Schizophrenia is a chronic mental disorder with devastating and disruptive personal, family, and social consequences, which affects about 1.1% of the world population above 18 years of age. In any given year, more than 2.4 million Americans and about 52 million individuals in the world suffer from pathologies associated with schizophrenia (SZ). The etiology of SZ is not completely understood and its complex neurobiology has been partly responsible for the lack of treatments to effectively treat the disease symptoms. Current medications and treatments ameliorate some of the disease symptoms;however, core pathologies of SZ (negative symptoms and cognitive deficits) are not affected. In addition, current medications suffer from serious side effects that limit their use by patients. Therefore, there remains a critical unmet need to identify and understand brain mechanisms effective in treating the negative and cognitive symptoms of SZ. We have identified Brain KCNQ (Kv7) voltage-gated potassium channels as unique signaling mechanism capable of ameliorating the negative and cognitive symptoms of SZ. These ion channels are widely expressed in the brain and are critically located in brain regions associated with SZ dysfunctions. The KCNQ potassium channels possess unique functional properties that allow them to be important regulators of neuronal and network activity in the brain. Our preliminary data strongly suggest that these channels can ameliorate behavioral deficits in animal models of SZ. In this proposal, we seek to characterize the role of prefrontal cortex KCNQ potassium channels in negative and cognitive symptoms associated with SZ. In addition, we will use the novel technique of multisite electrophysiological recording to study brain network activity under normal and disease states and determine the role of KCNQ potassium channels in modulating their activity. Therefore, in Aim 1, intracerebral microinfusion of KCNQ channel activators and blockers will be used to ascertain the role of prefrontal cortex channels in regulating aberrant behaviors associated with SZ. We will also take advantage of a developmental animal model of SZ (Methylazoxymethanol acetate, MAM) to test our hypothesis on the role of KCNQ channels.
In Aim 2, we will use simultaneous multicell multisite electrophysiological recording from hippocampus and prefrontal cortex of freely moving behaving animals engaged in a cognitive task to characterize the network activity in these two structures as well as their mutual interactions under control and disease states (using acute PCP animal model). In addition, we will monitor the network responses to modulation of KCNQ potassium channels. Lastly, we will record from hippocampus and prefrontal cortex of MAM treated rats and their response to modulation of KCNQ potassium channels. These studies will provide a unique opportunity to investigate the role of an important brain signaling mechanism, the KCNQ channel, in pathology of SZ using behavioral, cellular, and neuronal network analysis. The overall goal of this research project is in support of the NIMH mission to promote research and progress on the causes of mental disorders.

Public Health Relevance

Schizophrenia is a chronic mental disorder with devastating and disruptive personal, family, and social consequences, which affects about 1.1% of the world population above 18 years of age. In any given year, more than 2.4 million Americans and about 52 million individuals in the world suffer from pathologies associated with schizophrenia. Current medications ameliorate some symptoms of the disease (hallucinations, delusions, thought disorders), but are ineffective against other core symptoms (flat affect, avolition, memory and attention deficits, social withdrawal). Moreover, the side effects of current medications have limited the usefulness of these treatments. The brain KCNQ potassium channels are powerful regulators of brain network activity and, therefore, are uniquely positioned to monitor and regulate information processing and mutual interactions of brain regions implicated in pathology of schizophrenia. These channels will be studied in order to access their promise as novel brain targets for the development of therapies for the core symptoms of schizophrenia without serious side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH103775-01A1
Application #
8824412
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Winsky, Lois M
Project Start
2014-09-10
Project End
2016-08-31
Budget Start
2014-09-10
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$235,648
Indirect Cost
$54,216
Name
Marquette University
Department
Other Basic Sciences
Type
Schools of Allied Health Profes
DUNS #
046929621
City
Milwaukee
State
WI
Country
United States
Zip Code
53201