Schizophrenia is a debilitating neurological disorder with a world-wide prevalence of 1%. There is a strong genetic component with an estimated heritability of 80-85%. In the last decade, there has been unprecedented progress in identifying schizophrenia susceptibility genes, but the effect sizes of individual genes have been meager. Earlier studies have suggested that a primate and brain selective isoform (3.1) of the KCNH2 potassium channel is a factor in the brain dysfunction associated with schizophrenia. However, the critical molecular, cellular and neural network mechanisms related to KCNH2-3.1 and their relationship to the pathogenesis of schizophrenia are largely unknown. A KCNH2-3.1 isoform transgenic mouse has recently been made. This study defines the role of KCNH2-3.1 in the development of schizophrenia related cortical circuits, and illuminates critical issues in the time course of schizophrenia and provides support for a clinically important early treatment strategy and drug development. To test the central hypothesis that KCNH2-3.1 represents a key element not only for acute changes in cell firing patterns but also for long-term aberrant neurobiology by enhancing intrinsic neuronal vulnerability and the formation of impaired neural connections, the following three specific aims will be carried out: (1) In vitro electrophysiologicl and imaging studies of tissues taken from animal with extensive behavioral and cognitive phenotype will identify whether deficits in both sustained neuronal firing and neuronal synchronized activity in the prefrontal cortex (PFC) contribute to working memory deficits in the KCNH2-3.1 mice. Neuronal sustained firing and synchronized activity in the PFC are thought to reflect the cellular mechanisms critical for working memory dysfunction, which is considered to be a core feature of schizophrenia. (2) In vitro brain slices prepared from animals with extensive behavioral and cognitive phenotypes will be examined to determine whether behavioral deficits in these mice as adults reflect long-term dysfunction of neuronal structural plasticity in the PFC and hippocampus. (3) Telemetric EEG recording, the pHluorin assay and Inscopix's miniature in vivo brain imaging technology will be applied to determine whether selective impairments in neural connections between hippocampus and mPFC develop in these mice, as has also been implicated in schizophrenia. In addition, this work will answer the following questions: what are the time window changes in altering dendritic spines of prefrontal cortex and hippocampus described in these mice? What time window is best for antipsychotic drugs intervention? Which intracellular signaling pathways are involved in KCNH2-3.1-mediated structural plasticity and working memory deficits? Answers to these questions will identify targets for early therapeutic intervention that may be an effective way to avoid progressive synaptic structural and behavioral deterioration in patients with schizophrenia. The neural circuit studies in mutant KCNH2-3.1 mice will also be important and necessary for developing new drug treatments based on causation rather than phenomenology.

Public Health Relevance

Schizophrenia is one of the most disabling illnesses of world societies, yet all current treatments are based on a pharmacological model that is over 50 years old. The mechanistic studies of a promising animal model of schizophrenia based on the discovery of a novel KCNH2-3.1 channel offer unique potential to make progress in this direction. The application of electrophysiological, imaging and molecular analyses combined with animal behavioral testing can discover new targets for treatments and help biomedical scientists understand schizophrenia mechanisms.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Osborn, Bettina D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Lieber Institute, Inc.
United States
Zip Code