Bodarky CL, Halene TB, Ehrlichman RS, Banerjee A, Ray R, Hahn CG, Jonak G, Siegel SJ
Novel Environment and GABA Agonists Alter ERPs in NMDA NR1 Hypomorphic and Wild-type Mice. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Jul 14.
Background: Clinical and experimental data suggest dysregulation of NMDAR-mediated glutamatergic pathways in schizophrenia. The interaction between NMDAR-mediated abnormalities and the response to novel environment have not been studied.
Methods: Mice expressing 5-10% of normal NR1 subunits (NR1(neo)-/-) were compared to wild-type littermates for P20 and N40 auditory ERPs. Groups were tested for habituation within and across five testing sessions, with novel environment tested during a sixth session. Subsequently, we examined the effects of a GABAA positive allosteric modulator (chlordiazepoxide) and a GABAB receptor agonist (baclofen) as potential interventions to normalize aberrant responses.
Results: There was a reduction in P20, but not N40 amplitude within each habituation day. While there was no amplitude or gating change across habituation days, there was a reduction in P20 and N40 amplitude and gating in the novel environment. There was no difference between genotypes for N40. Only NR1(neo)-/- mice had reduced P20 in the novel environment. Chlordiazepoxide increased N40 amplitude in wild-type mice, while baclofen increased P20 amplitude in NR1(neo)-/- mice.
Conclusions: As noted in previous publications, the pattern of ERPs in NR1(neo)-/- mice does not recapitulate abnormalities in schizophrenia. Additionally, reduced NR1 expression does not influence N40 habituation, but does affect P20 in a novel environment. Thus, the pattern of P50 but not N100 in human studies may relate to subjects' reactions to unfamiliar environments. Additionally, NR1 reduction decreased GABAA receptor-mediated effects on ERPs while causing increased GABAB receptor-mediated effects. Future studies will examine changes in GABA receptor subunits following reductions in NR1 expression.
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