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

被引:31
作者
Gaskin, Philip L. R. [1 ]
Toledo-Rodriguez, Maria [1 ]
Alexander, Stephen P. H. [1 ]
Fone, Kevin C. F. [1 ,2 ]
机构
[1] Univ Nottingham, Sch Life Sci, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England
[2] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge, England
基金
英国生物技术与生命科学研究理事会;
关键词
isolation rearing; lamotrigine; microarray; phencyclidine; schizophrenia; glutamate; ISOLATION-REARED RATS; PREFRONTAL CORTEX; PREPULSE INHIBITION; OBJECT RECOGNITION; IMMUNE ACTIVATION; PARVALBUMIN IMMUNOREACTIVITY; SCHIZOAFFECTIVE DISORDER; COGNITIVE IMPAIRMENT; ANTIEPILEPTIC DRUGS; LAMOTRIGINE BLOCKS;
D O I
10.1093/ijnp/pyw062
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 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. Methods: Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10 mg/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. Results: Acute lamotrigine (10-15 mg/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. Conclusions: 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.
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页数:13
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