Temporal dysregulation of cortical gene expression in the isolation reared Wistar rat.
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.
Murphy
Keith J
KJ
Applied Neurotherapeutics Research Group, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland. keith.murphy@ucd.ie
Ter Horst
Judith P F
JP
Cassidy
Andrew W
AW
DeSouza
Ian E J
IE
Morgunova
Marina
M
Li
Christine
C
Connole
Laura M
LM
O'Sullivan
Niamh C
NC
Loscher
Jennifer S
JS
Brady
Angela T
AT
Rombach
Nanette
N
Connellan
Joanna
J
McGettigan
Paul A
PA
Scully
Darren
D
Fedriani
Rocio
R
Lukasz
Bartlomiej
B
Moran
Mary P
MP
McCabe
Olive M
OM
Wantuch
Caitlin M
CM
Hughes
Zoe A
ZA
Mulvany
Sean K
SK
Higgins
Desmond G
DG
Pangalos
Menelas N
MN
Marquis
Karen L
KL
O'Connor
William T
WT
Ring
Robert H
RH
von Schack
David
D
Regan
Ciaran M
CM
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
D018075:RNA, Complementary; D014157:Transcription Factors; D012313:RNA; D004247:DNA