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J Neurosci. 2016 Apr 27;36(17):4859-75. doi: 10.1523/JNEUROSCI.4632-15.2016.

Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model.

Author information

1
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, Genova 16163, Italy.
2
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland 21205.
3
University of Colorado, School of Medicine, Department of Psychiatry, Aurora, Colorado 80045.
4
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, Laboratory of Molecular Biology, Department of Surgical, Medical and Molecular Pathology and of Critical Care, University of Pisa, Pisa I-56126, Italy.
5
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850.
6
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892.
7
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland 21205, Departments of Psychiatry, Neurology, and Neuroscience, and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, and.
8
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, University of Colorado, School of Medicine, Department of Psychiatry, Aurora, Colorado 80045, University of Colorado, School of Medicine, Department of Cell and Developmental Biology, Aurora, Colorado 80045 amanda.law@ucdenver.edu.

Abstract

Schizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110δ, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory-inhibitory balance. Pharmacological inhibition of p110δ reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110δ as a target for antipsychotic drug development.

SIGNIFICANCE STATEMENT:

Schizophrenia is a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk for schizophrenia have been identified. Understanding how these genes affect brain development and function is necessary. This work is the first report of a newly generated humanized transgenic mouse model engineered to express human NRG1-IV, an isoform of the NRG1 (Neuregulin 1) gene that is increased in the brains of patients with schizophrenia in association with genetic risk. Using behavioral neuroscience, molecular biology, electrophysiology, and pharmacology, we identify a role for NRG1-IV in learning, memory, and cognition and determine that this relates to brain excitatory-inhibitory balance and changes in ErbB4/PI3K/AKT signaling. Moreover, the study further highlights the potential of targeting the PI3K pathway for the treatment of schizophrenia.

KEYWORDS:

AKT; ErbB; IC87114; PIK3CD; neuregulin; schizophrenia

PMID:
27122041
PMCID:
PMC4846677
DOI:
10.1523/JNEUROSCI.4632-15.2016
[Indexed for MEDLINE]
Free PMC Article

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