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

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Gaskin, Philip L.R., Toledo-Rodriguez, Maria, Alexander, Stephen P.H. and Fone, Kevin C.F. (2016) 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 . ISSN 1469-5111

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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.

Item Type: Article
RIS ID: https://nottingham-repository.worktribe.com/output/800791
Keywords: Isolation Rearing, Lamotrigine, Microarray, Phencyclidine, Schizophrenia, Glutamate
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: 10.1093/ijnp/pyw062
Depositing User: Fone, Kevin
Date Deposited: 19 Oct 2016 09:59
Last Modified: 04 May 2020 18:01
URI: https://eprints.nottingham.ac.uk/id/eprint/37102

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