Temporal dysregulation of cortical gene expression in the isolation reared Wistar rat

• Published in: Journal of neurochemistry Vol. 113; no. 3; pp. 601 - 614
• Main Authors: Murphy, Keith J, ter Horst, Judith P.F, Cassidy, Andrew W, DeSouza, Ian E.J, Morgunova, Marina, Li, Christine, Connole, Laura M, O'Sullivan, Niamh C, Loscher, Jennifer S, Brady, Angela T, Rombach, Nanette, Connellan, Joanna, McGettigan, Paul A, Scully, Darren, Fedriani, Rocio, Lukasz, Bartlomiej, Moran, Mary P, McCabe, Olive M, Wantuch, Caitlin M, Hughes, Zoe A, Mulvany, Sean K, Higgins, Desmond G, Pangalos, Menelas N, Marquis, Karen L, O'Connor, William T, Ring, Robert H, von Schack, David, Regan, Ciaran M
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.05.2010; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: Adult and adolescent clinical studies; Animals; Behavior, Animal - physiology; Biological and medical sciences; Cerebral Cortex - chemistry; Cerebral Cortex - metabolism; Cerebral Cortex - ultrastructure; Computational Biology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA - biosynthesis; DNA - genetics; Gene expression; Gene Expression Regulation - physiology; Interferon; Male; Medical sciences; Mental disorders; microarray analysis; Microdialysis; Motor Activity - physiology; Multigene Family; Neurochemistry; Neurology; Oligonucleotide Array Sequence Analysis; pre-pulse inhibition; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA - biosynthesis; RNA - genetics; RNA, Complementary - biosynthesis; RNA, Complementary - genetics; Rodents; Schizophrenia; Social Isolation - psychology; Stress, Psychological - genetics; Stress, Psychological - psychology; Synapses - physiology; Transcription Factors; ultrastructure; Animal model; microarray analysis; Rat; Central nervous system; Schizophrenia; Encephalon; Psychosis; Postnatal; Ultrastructure; pre-pulse inhibition; Rodentia; Prefrontal cortex; Gene expression; Vertebrata; Synapse; Mammalia; microdialysis; Animal; Excitatory aminoacid; Neurotransmitter; Mental disorder; Disruption; Glutamatergic transmission; Neurotransmission; Immediate early gene
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06617.x

J. Neurochem. (2010) 113, 601-614. 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.