TY - JOUR
T1 - Blockage of VIP during mouse embryogenesis modifies adult behavior and results in permanent changes in brain chemistry
AU - Hill, Joanna M.
AU - Hauser, Janet M.
AU - Sheppard, Lia M.
AU - Abebe, Daniel
AU - Spivak-Pohis, Irit
AU - Kushnir, Michal
AU - Deitch, Iris
AU - Gozes, Illana
N1 - Funding Information:
This research was supported in part by the Intramural Research Program of the NIH, NICHD, the US-Israel Binational Science Foundation, the Combined Program of the National Institutes of Health and the Sackler Faculty of Medicine/Tel-Aviv University in Women’s Health, the Israel Science Foundation, and Allon Therapeutics Inc. Professor Illana Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, heads the Adams Super Center for Brain Studies, the Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, and serves as the Chief Scientific Officer of Allon Therapeutics, Inc. We gratefully acknowledge Leslie R. Powell, Sandra Flores, Dana Paggett, Nicholas Tompkins, and Elizabeth Moody for their assistance in these studies.
PY - 2007/3
Y1 - 2007/3
N2 - Vasoactive intestinal peptide (VIP) regulates growth and development during the early postimplantation period of mouse embryogenesis. Blockage of VIP with a VIP antagonist during this period results in growth restriction, microcephaly, and developmental delays. Similar treatment of neonatal rodents also causes developmental delays and impaired diurnal rhythms, and the adult brains of these animals exhibit neuronal dystrophy and increased VIP binding. These data suggest that blockage of VIP during the development of the nervous system can result in permanent changes to the brain. In the current study, pregnant mice were treated with a VIP antagonist during embryonic days 8 through 10. The adult male offspring were examined in tests of novelty, paired activity, and social recognition. Brain tissue was examined for several measures of chemistry and gene expression of VIP and related compounds. Glial cells from the cortex of freated newborn mice were plated with neurons and examined for VIP binding and their ability to enhance neuronal survival. Treated adult male mice exhibited increased anxiety-like behavior and deficits in social behavior. Brain tissue exhibited regionally specific changes in VIP chemistry and a trend toward increased gene expression of VIP and related compounds that reached statistical significance in the VIP receptor, VPAC-1, in the female cortex. When compared to control astrocytes, astrocytes from treated cerebral cortex produced further increases in neuronal survival with excess synaptic connections and reduced VIP binding. In conclusion, impaired VIP activity during mouse embryogenesis resulted in permanent changes to both adult brain chemistry/cell biology and behavior with aspects of autism-like social deficits.
AB - Vasoactive intestinal peptide (VIP) regulates growth and development during the early postimplantation period of mouse embryogenesis. Blockage of VIP with a VIP antagonist during this period results in growth restriction, microcephaly, and developmental delays. Similar treatment of neonatal rodents also causes developmental delays and impaired diurnal rhythms, and the adult brains of these animals exhibit neuronal dystrophy and increased VIP binding. These data suggest that blockage of VIP during the development of the nervous system can result in permanent changes to the brain. In the current study, pregnant mice were treated with a VIP antagonist during embryonic days 8 through 10. The adult male offspring were examined in tests of novelty, paired activity, and social recognition. Brain tissue was examined for several measures of chemistry and gene expression of VIP and related compounds. Glial cells from the cortex of freated newborn mice were plated with neurons and examined for VIP binding and their ability to enhance neuronal survival. Treated adult male mice exhibited increased anxiety-like behavior and deficits in social behavior. Brain tissue exhibited regionally specific changes in VIP chemistry and a trend toward increased gene expression of VIP and related compounds that reached statistical significance in the VIP receptor, VPAC-1, in the female cortex. When compared to control astrocytes, astrocytes from treated cerebral cortex produced further increases in neuronal survival with excess synaptic connections and reduced VIP binding. In conclusion, impaired VIP activity during mouse embryogenesis resulted in permanent changes to both adult brain chemistry/cell biology and behavior with aspects of autism-like social deficits.
KW - Activity-dependent neuroprotective protein (ADNP)
KW - Anxiety-like behavior
KW - Autism
KW - Neurodevelopmental disorders
KW - Neuronal survival
KW - Social behavior
KW - Synaptogenesis
UR - http://www.scopus.com/inward/record.url?scp=34548320851&partnerID=8YFLogxK
U2 - 10.1385/jmn:31:03:185
DO - 10.1385/jmn:31:03:185
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AN - SCOPUS:34548320851
SN - 0895-8696
VL - 31
SP - 183
EP - 200
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 3
ER -