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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

Gaskin, Philip L.R.; Toledo-Rodriguez, Maria; Alexander, Stephen P.H.; Fone, Kevin C.F.

Authors

Philip L.R. Gaskin plrgaskin@gmail.com

Maria Toledo-Rodriguez Maria.Toledo@nottingham.ac.uk

Stephen P.H. Alexander Steve.Alexander@nottingham.ac.uk

Kevin C.F. Fone kevin.fone@nottingham.ac.uk



Abstract

Background: 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 characterise alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model.

Methods: Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10 mg/kg, s.c.), on post-natal day (PND) 7, 9 and 11 before being weaned on PND 23 into separate cages (isolation, PCP-SI, n=31), or 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 (PND60-75) and drug-free hippocampal gene expression on PND70.

Results: 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 signalling, and in specific schizophrenia-linked genes, including PVALB and GAD67, in PCP-SI rats which resemble changes reported in schizophrenia.

Conclusions: Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism and GABA signalling 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.

Journal Article Type Article
Journal International Journal of Neuropsychopharmacology
Print ISSN 1461-1457
Electronic ISSN 1469-5111
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
APA6 Citation Gaskin, P. L., Toledo-Rodriguez, M., Alexander, S. P., & Fone, K. C. (in press). 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. International Journal of Neuropsychopharmacology, doi:10.1093/ijnp/pyw062
DOI https://doi.org/10.1093/ijnp/pyw062
Keywords Isolation Rearing, Lamotrigine, Microarray, Phencyclidine, Schizophrenia, Glutamate
Publisher URL http://ijnp.oxfordjournals.org/content/early/2016/07/15/ijnp.pyw062
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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