N-methyl-d-aspartic acid receptor antagonist-induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia.

INTRODUCTION: Electrophysiological responses to auditory stimuli have provided a useful means of elucidating mechanisms and evaluating treatments in psychiatric disorders. Deficits in gating during paired-click tasks and lack of mismatch negativity following deviant stimuli have been well characterized in patients with schizophrenia. Recently, analyses of basal, induced, and evoked frequency oscillations have gained support as additional measures of cognitive processing in patients and animal models. The purpose of this study is to examine frequency oscillations in mice across the theta (4-7.5 Hz) and gamma (31-61 Hz) bands in the context of N-methyl-d-aspartic acid receptor (NMDAR) hypofunction and dopaminergic hyperactivity, both of which are thought to serve as pharmacological models of schizophrenia. EXPERIMENTAL PROCEDURES: Electroencephalograms (EEG) were recorded from mice in five treatment groups that consisted of haloperidol, risperidone, amphetamine, ketamine, or ketamine plus haloperidol during an auditory task. Basal, induced and evoked powers in both frequencies were calculated. RESULTS: Ketamine increased basal power in the gamma band and decreased the evoked power in the theta band. The increase in basal gamma was not blocked by treatment with a conventional antipsychotic. No other treatment group was able to fully reproduce this pattern in the mice. CONCLUSIONS: Ketamine-induced alterations in EEG power spectra are consistent with abnormalities in the theta and gamma frequency ranges reported in patients with schizophrenia. Our findings support the hypothesis that NMDAR hypofunction contributes to the deficits in schizophrenia and that the dopaminergic pathways alone may not account for these changes.

Mice expressing constitutively active Gsalpha exhibit stimulus encoding deficits similar to those observed in schizophrenia patients.

People with schizophrenia display sensory encoding deficits across a broad range of electrophysiological and behavioral measures, suggesting fundamental impairments in the ability to transduce the external environment into coherent neural representations. This inability to create basic components of complex stimuli interferes with a high fidelity representation of the world and likely contributes to cognitive deficits. The current study evaluates the effects of constitutive forebrain activation of the G(s)alpha G-protein subunit on auditory threshold and gain using acoustic brainstem responses and cortically generated N40 event-related potentials to assess the role of cyclic AMP signaling in sensory encoding. Additionally, we examine the ability of pharmacological treatments that mimic (amphetamine) or ameliorate (haloperidol) positive symptoms of schizophrenia to test the hypothesis that the encoding deficits observed in G(s)alpha transgenic mice can be normalized with treatment. We find that G(s)alpha transgenic mice have decreased amplitude of cortically generated N40 but normal acoustic brainstem response amplitude, consistent with forebrain transgene expression and a schizophrenia endophenotype. Transgenic mice also display decreased stimulus intensity response (gain) in both acoustic brainstem response and N40, indicating corticofugal influence on regions that lack transgene expression. N40 deficits in transgenic animals were ameliorated with low dose haloperidol and reversed with higher dose, suggesting dopamine D2 receptor-linked Gi activity contributes to the impairment. Consistent with this hypothesis, we recreated the G(s)alpha transgenic deficit in wild type animals using the indirect dopamine agonist amphetamine. This transgenic model of sensory encoding deficits provides a foundation for identifying biochemical contributions to sensory processing impairments associated with schizophrenia.

Monoamine reuptake inhibition and nicotine receptor antagonism reduce amplitude and gating of auditory evoked potentials.

BACKGROUND: Sensory encoding deficits have been extensively studied as endophenotypic markers of schizophrenia using auditory evoked potentials. In order to increase understanding of the neurochemical basis of such deficits, we utilized an animal model to test whether monoamine reuptake inhibition and nicotine receptor antagonism reduce the amplitude and gating of the P20 and N40 auditory components. METHODS: C57BL/6J mice received 12 days of chronic vehicle, bupropion, haloperidol or bupropion plus haloperidol. Auditory evoked potentials were then recorded in alert mice to measure the amplitude and gating of evoked components during a paired click paradigm similar to tasks used to measure the P50 and N100 auditory potentials in schizophrenia. Evoked potentials were recorded prior to and following acute nicotine. RESULTS: Bupropion reduced the amplitude and gating of the N40 evoked potential in mice, similar to the P50 and N100 endophenotypes associated with sensory encoding deficits in schizophrenia. This deficit was fully reversed only by the combination of haloperidol and nicotine, suggesting that dopamine reuptake inhibition and nicotine antagonism both contribute to the observed phenotype. Furthermore, nicotine increased P20 amplitude across all groups supporting a role for nicotine agonists in pre-attentive sensory encoding deficits. CONCLUSIONS: We propose that the combination of monoamine inhibition and nicotine receptor antagonism may serve as a useful model for preclinical screening of pharmaceutical compounds aimed at treating sensory encoding deficits in schizophrenia.

Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications.

OVERVIEW: All current antipsychotic medications work by binding to Gi-coupled dopamine (DA) D2 receptors. Such medications are thought to affect cellular function primarily by decreasing DA-mediated regulation of intracellular cyclic adenosine monophosphate (cAMP).However, several studies indicate that cAMP signal transduction abnormalities in schizophrenia may not be limited to D2-containing cells. The current study examines the potential of using non-receptor-based agents that modify intracellular signal transduction as potential antipsychotic medications. METHODS: The indirect DA agonist amphetamine has been used to model the auditory sensory processing deficits in schizophrenia. Such pharmacologically induced abnormalities are reversed by current antipsychotic treatments. This study examines the ability of the phosphodiesterase-4 inhibitor, rolipram, to reverse amphetamine-induced abnormalities in auditory-evoked potentials that are characteristic of schizophrenia. RESULTS: Rolipram reverses amphetamine-induced reductions in auditory-evoked potentials. CONCLUSION: This finding could lead to novel approaches to receptor-independent treatments for schizophrenia.