期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 17, 页码 4859-4875出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4632-15.2016
关键词
AKT; ErbB; IC87114; neuregulin; PIK3CD; schizophrenia
资金
- National Institute of Mental Health (NIMH) Intramural Research Program, National Institutes of Health (NIH)
- NIH, NIMH [P50 MH-086383-06, R01 MH103716-02]
- Brain and Behavior Research Foundation/NARSAD
- Dr. Nancy Gary Endowed Chair in Children's Mental Health Disorders
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-p110 delta, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory-inhibitory balance. Pharmacological inhibition of p110 delta 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 p110 delta as a target for antipsychotic drug development.
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