title: Insulin-Like Growth Factor I Produces an Antidepressant-Like Effect and Elicits N-Methyl-D-Aspartate Receptor Independent Long-Term Potentiation of Synaptic Transmission in Medial Prefrontal Cortex and Hippocampus.
abstract: BACKGROUND
  Growth factors play an important role in regulating neurogenesis and synapse formation and may be involved in regulating the antidepressant response to conventional antidepressants. To date, Insulin-like growth factor I (IGFI) is the only growth factor that has shown antidepressant properties in human clinical trials. However, its mechanism of action remains unclear.
  
  
  METHODS
  The antidepressant-like effect of a single IV dose of IGFI was determined using a chronic unpredictable stress paradigm in the rat Porsolt, sucrose preference, novelty-induced hypophagia, and ultrasonic vocalization models. The dependence of the medial prefrontal cortex for these effects was determined by direct medial prefrontal cortex injection followed by Porsolt testing as well as IGFI receptor activation in the medial prefrontal cortex following an optimal IV antidepressant-like dose of IGFI. The effect of IGFI on synaptic transmission and long-term potentiation (LTP) of synaptic strength was assessed in the hippocampus and medial prefrontal cortex. The dependence of these effects on IGFI and AMPA receptor activation and protein synthesis were also determined.
  
  
  RESULTS
  IGFI produced a rapid-acting and long-lasting antidepressant-like effect in each of the depression models. These effects were blocked by IGFI and AMPA receptor antagonists, and medial prefrontal cortex was localized. IGFI robustly increased synaptic strength in the hippocampus and medial prefrontal cortex and these effects were IGFI receptor and protein synthesis-dependent but N-methyl-d-aspartate receptor independent. IGFI also robustly facilitated hippocampal metaplasticity 24 hours postdosing.
  
  
  CONCLUSIONS
  These data support the conclusion that the antidepressant-like effects of IGFI are mediated by a persistent, LTP-like enhancement of synaptic strength requiring both IGFIR activation and ongoing protein synthesis.
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL (Drs Burgdorf and Moskal); Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY (Drs Zhang and Stanton); Naurex Inc., Evanston, IL (Dr Colechio, Mrs Ghoreishi-Haack, Dr Gross, Dr Kroes, and Dr Moskal). j-burgdorf@northwestern.edu.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Burgdorf
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL (Drs Burgdorf and Moskal); Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY (Drs Zhang and Stanton); Naurex Inc., Evanston, IL (Dr Colechio, Mrs Ghoreishi-Haack, Dr Gross, Dr Kroes, and Dr Moskal).
authors.forename: Xiao-lei
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL (Drs Burgdorf and Moskal); Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY (Drs Zhang and Stanton); Naurex Inc., Evanston, IL (Dr Colechio, Mrs Ghoreishi-Haack, Dr Gross, Dr Kroes, and Dr Moskal).
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Colechio
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL (Drs Burgdorf and Moskal); Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY (Drs Zhang and Stanton); Naurex Inc., Evanston, IL (Dr Colechio, Mrs Ghoreishi-Haack, Dr Gross, Dr Kroes, and Dr Moskal).
authors.forename: Nayereh
authors.initials: N
authors.lastname: Ghoreishi-Haack
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL (Drs Burgdorf and Moskal); Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY (Drs Zhang and Stanton); Naurex Inc., Evanston, IL (Dr Colechio, Mrs Ghoreishi-Haack, Dr Gross, Dr Kroes, and Dr Moskal).
authors.forename: Amanda
authors.initials: A
authors.lastname: Gross
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL (Drs Burgdorf and Moskal); Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY (Drs Zhang and Stanton); Naurex Inc., Evanston, IL (Dr Colechio, Mrs Ghoreishi-Haack, Dr Gross, Dr Kroes, and Dr Moskal).
authors.forename: Roger A
authors.initials: RA
authors.lastname: Kroes
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL (Drs Burgdorf and Moskal); Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY (Drs Zhang and Stanton); Naurex Inc., Evanston, IL (Dr Colechio, Mrs Ghoreishi-Haack, Dr Gross, Dr Kroes, and Dr Moskal).
authors.forename: Patric K
authors.initials: PK
authors.lastname: Stanton
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL (Drs Burgdorf and Moskal); Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY (Drs Zhang and Stanton); Naurex Inc., Evanston, IL (Dr Colechio, Mrs Ghoreishi-Haack, Dr Gross, Dr Kroes, and Dr Moskal).
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Moskal
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008845:Microinjections; D009924:Organ Culture Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D016194:Receptors, N-Methyl-D-Aspartate; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I
keywords: LTP; N-methyl-d-aspartate receptor; NMDAR; depression; insulin-like growth factor I; long-term potentiation; synaptic plasticity