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.

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.

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, https://doi.org/10.1093/ijnp/pyw062

• Journal Article Type: Article
• Acceptance Date: Jun 27, 2016
• Online Publication Date: Jul 15, 2016
• Deposit Date: Oct 19, 2016
• Publicly Available Date: Oct 19, 2016
• Journal: International Journal of Neuropsychopharmacology
• Print ISSN: 1461-1457
• Electronic ISSN: 1469-5111
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1093/ijnp/pyw062
• Keywords: Isolation Rearing, Lamotrigine, Microarray, Phencyclidine, Schizophrenia, Glutamate
• Public URL: https://nottingham-repository.worktribe.com/output/800791
• Publisher URL: http://ijnp.oxfordjournals.org/content/early/2016/07/15/ijnp.pyw062
• Contract Date: Oct 19, 2016