title: Reductions in synaptic proteins and selective alteration of prepulse inhibition in male C57BL/6 mice after postnatal administration of a VIP receptor (VIPR2) agonist.
abstract: BACKGROUND
  An abundance of genetic and epidemiologic evidence as well as longitudinal neuroimaging data point to developmental origins for schizophrenia and other mental health disorders. Recent clinical studies indicate that microduplications of VIPR2, encoding the vasoactive intestinal peptide (VIP) receptor VPAC2, confer significant risk for schizophrenia and autism spectrum disorder. Lymphocytes from patients with these mutations exhibited higher VIPR2 gene expression and VIP responsiveness (cAMP induction), but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown.
  
  
  OBJECTIVE
  We subcutaneously administered the highly selective VPAC2 receptor agonist Ro 25-1553 to C57BL/6 mice from postnatal day 1 (P1) to P14 to determine if overactivation of VPAC2 receptor signaling during postnatal brain maturation affects synaptogenesis and selected behaviors.
  
  
  RESULTS
  Western blot analyses on P21 revealed significant reductions of synaptophysin and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex, but not in the hippocampus in Ro 25-1553-treated mice. The same postnatally restricted treatment resulted in a disruption in prepulse inhibition of the acoustic startle measured in adult mice. No effects were observed in open-field locomotor activity, sociability in the three-chamber social interaction test, or fear conditioning or extinction.
  
  
  CONCLUSIONS
  Overactivation of the VPAC2 receptor in the postnatal mouse results in a reduction in synaptic proteins in the prefrontal cortex and selective alterations in prepulse inhibition. These findings suggest that the VIPR2-linkage to mental health disorders may be due in part to overactive VPAC2 receptor signaling during a critical time of synaptic maturation.
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, 635 Charles E. Young Drive South, Los Angeles, CA, 90095, USA.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.forename: Michael C
authors.initials: MC
authors.lastname: Condro
authors.forename: Yossan-Var
authors.initials: YV
authors.lastname: Tan
authors.forename: Cristina A
authors.initials: CA
authors.lastname: Ghiani
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Colwell
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Cushman
authors.forename: Michael S
authors.initials: MS
authors.lastname: Fanselow
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: James A
authors.initials: JA
authors.lastname: Waschek
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000076122:Disks Large Homolog 4 Protein; D005239:Fear / Q000187:drug effects; D005260:Female; D051528:Guanylate Kinases / Q000378:metabolism; D007398:Interpersonal Relations; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011247:Pregnancy; D065808:Prepulse Inhibition / Q000187:drug effects*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists*; D013216:Reflex, Startle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010456:Peptides, Cyclic; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; C089777:Ro 25-1553; D016708:Synaptophysin; C495510:Vipr2 protein, mouse; D014660:Vasoactive Intestinal Peptide; D051528:Guanylate Kinases