Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following
Philip Lr Gaskin1, Maria Toledo-Rodriguez1, Stephen Ph Alexander1
1School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, United Kingdom (Drs Gaskin, Toledo-Rodriguez, Alexander, and Fone).
Insights
This study shows that a rat model of schizophrenia exhibits altered neurotransmitter gene expression. Lamotrigine partially reversed behavioral deficits, suggesting potential for treating cognitive symptoms in schizophrenia.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Schizophrenia symptoms are linked to neurotransmitter dysfunction, including dopamine, GABA, and glutamate.
- A rat model combining phencyclidine (PCP) and social isolation mimics core schizophrenia symptoms.
- This model allows investigation of hippocampal gene expression and potential therapeutic interventions.
Purpose of the Study:
- To characterize hippocampal neurotransmitter-related gene expression changes in a rat model of schizophrenia.
- To evaluate the efficacy of lamotrigine in reversing behavioral deficits in this model.
- To explore lamotrigine's potential as an adjunctive therapy for schizophrenia.
Main Methods:
- Rats received neonatal PCP injections and post-weaning social isolation (PCP-SI) or were group-housed (V-GH).
- Behavioral tests assessed locomotor activity, novel object recognition, and prepulse inhibition.
- Hippocampal gene expression was analyzed using DNA microarrays.
Main Results:
- Lamotrigine reversed PCP-SI-induced hyperactivity and novel object recognition deficits.
- Lamotrigine did not improve the prepulse inhibition deficit.
- Microarray analysis revealed down-regulation of glutamate metabolism, dopamine, and GABA signaling genes, including PVALB and GAD67, in PCP-SI rats.
Conclusions:
- Neurotransmitter system alterations in the hippocampus contribute to behavioral deficits in the PCP-SI model.
- Lamotrigine shows potential for improving specific cognitive deficits in schizophrenia.
- Further research is warranted to explore lamotrigine's therapeutic role.
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, 10mg/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 (10-15mg/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 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.
