title: Temporal dysregulation of cortical gene expression in the isolation reared Wistar rat.
abstract: The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon-associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, Nsf, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness.
authors.affiliation: Applied Neurotherapeutics Research Group, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland. keith.murphy@ucd.ie
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Murphy
authors.forename: Judith P F
authors.initials: JP
authors.lastname: Ter Horst
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Cassidy
authors.forename: Ian E J
authors.initials: IE
authors.lastname: DeSouza
authors.forename: Marina
authors.initials: M
authors.lastname: Morgunova
authors.forename: Christine
authors.initials: C
authors.lastname: Li
authors.forename: Laura M
authors.initials: LM
authors.lastname: Connole
authors.forename: Niamh C
authors.initials: NC
authors.lastname: O'Sullivan
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Loscher
authors.forename: Angela T
authors.initials: AT
authors.lastname: Brady
authors.forename: Nanette
authors.initials: N
authors.lastname: Rombach
authors.forename: Joanna
authors.initials: J
authors.lastname: Connellan
authors.forename: Paul A
authors.initials: PA
authors.lastname: McGettigan
authors.forename: Darren
authors.initials: D
authors.lastname: Scully
authors.forename: Rocio
authors.initials: R
authors.lastname: Fedriani
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Lukasz
authors.forename: Mary P
authors.initials: MP
authors.lastname: Moran
authors.forename: Olive M
authors.initials: OM
authors.lastname: McCabe
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Wantuch
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: Sean K
authors.initials: SK
authors.lastname: Mulvany
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Higgins
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marquis
authors.forename: William T
authors.initials: WT
authors.lastname: O'Connor
authors.forename: Robert H
authors.initials: RH
authors.lastname: Ring
authors.forename: David
authors.initials: D
authors.lastname: von Schack
authors.forename: Ciaran M
authors.initials: CM
authors.lastname: Regan
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D019295:Computational Biology; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000502:physiology; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012934:Social Isolation / Q000523:psychology*; D013315:Stress, Psychological / Q000235:genetics / Q000523:psychology; D013569:Synapses / Q000502:physiology; D014157:Transcription Factors
chemical_list: D018075:RNA, Complementary; D014157:Transcription Factors; D012313:RNA; D004247:DNA