title: Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia.
abstract: Dysfunction of dopaminergic, GABAergic, and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterize alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model.
  
  
  
  Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10mg/kg, s.c.) on post-natal days (PND) 7, 9, and 11 before being weaned on PND 23 into separate cages (isolation; PCP-SI; n = 31) or received vehicle injection and group-housing (2-4 per cage; V-GH; n = 23) from weaning. The effect of lamotrigine on locomotor activity, novel object recognition, and prepulse inhibition of acoustic startle was examined (PND 60-75) and drug-free hippocampal gene expression on PND 70.
  
  
  
  Acute lamotrigine (10-15mg/kg i.p.) reversed the hyperactivity and novel object recognition impairment induced by PCP-SI but had no effect on the prepulse inhibition deficit. Microarray revealed small but significant down-regulation of hippocampal genes involved in glutamate metabolism, dopamine neurotransmission, and GABA receptor signaling and in specific schizophrenia-linked genes, including parvalbumin (PVALB) and GAD67, in PCP-SI rats, which resemble changes reported in schizophrenia.
  
  
  
  Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism, and GABA signaling may contribute to some of the behavioral deficits observed following PCP-SI, and that lamotrigine may have some utility as an adjunctive therapy to improve certain cognitive deficits symptoms in schizophrenia.
authors.affiliation: School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, United Kingdom (Drs Gaskin, Toledo-Rodriguez, Alexander, and Fone).
authors.forename: Philip Lr
authors.initials: PL
authors.lastname: Gaskin
authors.affiliation: School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, United Kingdom (Drs Gaskin, Toledo-Rodriguez, Alexander, and Fone).
authors.forename: Maria
authors.initials: M
authors.lastname: Toledo-Rodriguez
authors.affiliation: School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, United Kingdom (Drs Gaskin, Toledo-Rodriguez, Alexander, and Fone).
authors.forename: Stephen Ph
authors.initials: SP
authors.lastname: Alexander
authors.affiliation: School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, United Kingdom (Drs Gaskin, Toledo-Rodriguez, Alexander, and Fone) kevin.fone@nottingham.ac.uk.
authors.forename: Kevin Cf
authors.initials: KC
authors.lastname: Fone
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000077213:Lamotrigine; D008124:Locomotion; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010622:Phencyclidine; D010641:Phenotype; D065808:Prepulse Inhibition; D011919:Rats, Inbred Strains; D021641:Recognition, Psychology; D013216:Reflex, Startle; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D012565:Schizophrenic Psychology; D012934:Social Isolation; D026941:Sodium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology; D014886:Weaning
chemical_list: D026941:Sodium Channel Blockers; D014227:Triazines; D018698:Glutamic Acid; D010622:Phencyclidine; D000077213:Lamotrigine
keywords: glutamate; isolation rearing; lamotrigine; microarray; phencyclidine; schizophrenia