The Effects of Ketamine Vary Among Inbred Mouse Strains and Mimic Schizophrenia for the P80, but not P20 or N40 Auditory ERP Components

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151

Several electrical neural oscillatory abnormalities have been associated with schizophrenia, although the underlying mechanisms of these oscillatory problems are unclear. Animal studies suggest that one of the key mechanisms of neural oscillations is through glutamatergic regulation; therefore, neural oscillations may provide a valuable animal-clinical interface on studying glutamatergic dysfunction in schizophrenia. To identify glutamatergic control of neural oscillation relevant to human subjects, we studied the effects of ketamine, an N-methyl-D-aspartate antagonist that can mimic some clinical aspects of schizophrenia, on auditory-evoked neural oscillations using a paired-click paradigm. This was a double-blind, placebo-controlled, crossover study of ketamine vs saline infusion on 10 healthy subjects. Clinically, infusion of ketamine in subanesthetic dose significantly increased thought disorder, withdrawal-retardation, and dissociative symptoms. Ketamine significantly augmented high-frequency oscillations (gamma band at 40-85 Hz, p ¼ 0.006) and reduced lowfrequency oscillations (delta band at 1-5 Hz, po0.001) compared with placebo. Importantly, the combined effect of increased gamma and reduced delta frequency oscillations was significantly associated with more withdrawal-retardation symptoms experienced during ketamine administration (p ¼ 0.02). Ketamine also reduced gating of the theta-alpha (5-12 Hz) range oscillation, an effect that mimics previously described deficits in schizophrenia patients and their first-degree relatives. In conclusion, acute ketamine appeared to mimic some aspects of neural oscillatory deficits in schizophrenia, and showed an opposite effect on scalp-recorded gamma vs low-frequency oscillations. These electrical oscillatory indexes of subanesthetic ketamine can be potentially used to cross-examine glutamatergic pharmacological effects in translational animal and human studies.

Section: Discussionsupporting

confidence: 84%

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

Hong

Summerfelt

Boyer

et al. 2009

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151

“…Additionally, we have included analysis of the P20 component in an attempt to further characterize the effects of antipsychotic treatment across a broader array of endophenotypic markers related to schizophrenia. Previous studies of a paired click-gating task in C57Bl/6J mice in our group found a mean amplitude of 26 mV for the P20 evoked potential (Connolly et al, 2004). Power analyses indicate that there is an 89% probability of detecting a meaningful difference of 10 mV (40%) of the expected mean, with a case correlation of 0.1 and a sample size of eight mice per group, as designed in the current report.…”

Section: Discussionsupporting

confidence: 59%

Effects of Chronic Olanzapine and Haloperidol Differ on the Mouse N1 Auditory Evoked Potential

Maxwell

Liang

Weightman

et al. 2004

Self Cite

Auditory evoked potentials have been used in a variety of animal models to assess information-processing impairments in schizophrenia. Previous mouse models have primarily employed a paired click paradigm to assess the transient measures of auditory gating. The current study uses stimulus trains at varied interstimulus intervals (ISI) between 0.25 and 8 s in mice to assess the effects of chronic olanzapine and haloperidol on auditory processing. Data indicate that olanzapine increases the amplitude of the N40, P80, and P20/N40 components of the auditory evoked potential, whereas haloperidol had no such effect. The ISI paradigm also allowed for an evaluation of several components of the mouse evoked potential to assess those that display response properties similar to the human P50 and N100. Data suggest that the mouse N40 displays an ISI response relationship that shares characteristics with the human N100, whereas the P20 appears more consistent with the human P50 across the ISI range evaluated in this task. This study suggests that olanzapine may help improve N100 impairments seen in schizophrenia, while haloperidol does not.

“…Furthermore, previous studies have shown that the mouse AEP peaks P1, N1, and P2 display refractory curves comparable to their putative human correlates (P1, N1, P2) (Umbricht et al, 2004b;Maxwell et al, 2004). Also, in two mouse studies that investigated the effects of pharmacological NMDAR blockade P1 was increased and N1 changed dependent on mouse strain (Maxwell et al, 2006;Connolly et al, 2004). However, since only one long ISI (9 s) was used in these studies, the effect of NMDAR antagonism on responses to tones with short ISIs in mice is unknown.…”

Section: Aep Peak Refractorinessmentioning

confidence: 72%

“…Early auditory sensory processing deficits in NR1 mutants S Bickel et al mutant mice was caused by reduced suppression of the response to the second tone (Figure 1). Based on previous studies, we reason that the mouse correlates of the P50 and N100 are the P20 and N40 respectively (named P1 and N1 in this paper) (Umbricht et al, 2004b;Connolly et al, 2004;Siegel et al, 2003). Most gating studies in humans have focused on the P50 component of the human auditory AEP and only few on the N100.…”

Section: Auditory Gatingmentioning

confidence: 94%

“…So far, most, but not all, studies in rats showed impairments of N40 -gating (the putative rat correlate of the human N100) with NMDAR blocking (Miller et al, 1992;de Bruin et al, 1999;Swerdlow et al, 2006). However, no effect of NMDAR antagonists on auditory gating was observed in a study in mice (Connolly et al, 2004). Furthermore, two studies in healthy human subjects showed no effect of ketamine on auditory gating (Oranje et al, 2002;van Berckel et al, 1998).…”

Section: Auditory Gatingmentioning

confidence: 99%

See 1 more Smart Citation

Early Auditory Sensory Processing Deficits in Mouse Mutants with Reduced NMDA Receptor Function

Bickel

Lipp

Umbricht

2007

Cognitive deficits in schizophrenia include impairments at automatic, preattentive stages of sensory information processing. These deficits are evident in the prepulse inhibition-(PPI) and habituation of the auditory startle response paradigm, the paired tone paradigm in the EEG, and the peak recovery function of auditory evoked potentials (AEP). Administration of NMDA receptor antagonists reliably disrupts PPI and habituation of the startle, but not gating of AEPs in rodents. In the peak recovery paradigm, patients with schizophrenia and primates treated with NMDA receptor antagonists show reduced maximal response at long interstimulus intervals (ISI), but normal responses at short ISIs. Thus reduced NMDA receptor signalling may underlie alterations in these paradigms observed in schizophrenia. We tested the paradigms mentioned in mouse mutants with reduced expression of the NR1 subunit of the NMDA receptor (N ¼ 15) and their wild-type littermates (N ¼ 16). The NR1 mutant mice showed impaired habituation and PPI of the auditory startle response, as well as impaired gating in the paired tone paradigm. Deficits between the two gating measures did not correlate, corroborating previous evidence that these paradigms measure distinct processes. In the peak recovery paradigm, the NR1 mutants showed increased responses of the AEPs P1 and N1 at short ISIs but no difference between groups were observed at long ISIs. In conclusion, the NR1 hypomorphic mice modelled sensory and sensorimotor gating and startle habituation deficits observed in schizophrenia, but failed to model alterations in the peak recovery function.