Behavioral, neurophysiological, and synaptic impairment in a transgenic neuregulin1 (NRG1-IV) murine schizophrenia model

Francesco Papaleo, Feng Yang, Clare Paterson, Sara Palumbo, Gregory Carr, Yanhong Wang, Kirsten Floyd, Wenwei Huang, Craig J. Thomas, Jingshan Chen, Daniel Weinberger, Amanda J. Law

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4859-4875
Number of pages17
JournalJournal of Neuroscience
Volume36
Issue number17
DOIs
Publication statusPublished - Apr 27 2016

    Fingerprint

Keywords

  • AKT
  • ErbB
  • IC87114
  • Neuregulin
  • PIK3CD
  • Schizophrenia

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this