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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
被引:31
作者:

Gaskin, Philip L. R.
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Nottingham, Sch Life Sci, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England Univ Nottingham, Sch Life Sci, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England

Toledo-Rodriguez, Maria
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h-index: 0
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Univ Nottingham, Sch Life Sci, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England Univ Nottingham, Sch Life Sci, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England

Alexander, Stephen P. H.
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h-index: 0
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Univ Nottingham, Sch Life Sci, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England Univ Nottingham, Sch Life Sci, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England

Fone, Kevin C. F.
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h-index: 0
机构:
Univ Nottingham, Sch Life Sci, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England
Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge, England Univ Nottingham, Sch Life Sci, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England
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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