Yuling Liang

GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction.

Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30–80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory–inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1neo−/− mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABAB-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.

Effects of strain, novelty, and NMDA blockade on auditory-evoked potentials in mice.

People with schizophrenia exhibit impaired ability to modify electroencephalographic event-related potential (ERP) responses to novel stimuli. These deficits serve as a window into the abnormalities of neuronal organization and function and are thought to reflect a component of genetic vulnerability for schizophrenia. We describe differences among inbred mouse strains for ERPs following a novelty detection paradigm, as a model for genetic contributions to disease vulnerability. Auditory-evoked potentials were recorded during an auditory oddball task in nonanesthetized C57BL/6J, C3H/HeJ, and DBA/2J mice prior to and following ketamine (10 mg/kg). Stimuli consisted of 80 sets of 24 standard tones followed by one novel tone. Principal component analysis yielded four temporal components that contribute to the auditory ERP responses to standard and novel stimuli. Two principal components that varied between standard and novel stimuli also differed among inbred mouse strains. Post hoc analyses indicate that strain effects on novelty detection are due to a significant difference between the response to novel and standard tones in C3H/HeJ mice that is absent in the other two strains. Inbred strains of mice vary in their ability to perform neuronal detection of change in the auditory environment. The ability to model novelty detection deficits in mice will aid in identifying genetic contributions to abnormal neuronal organization in people with schizophrenia.

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

N-methyl-D-aspartate (NMDA) antagonists produce behavioral and electrophysiological effects similar to schizophrenia. The mouse P20, N40, and P80 event related potential (ERP) components were analyzed for genetic variance among inbred strains and ketamine-induced differences to model abnormalities in the P50, N100, and P200 in schizophrenia. Ketamine increased P20/N40 amplitude and decreased P80 amplitude. Therefore, the effects of ketamine in mice are inconsistent with alterations in the corresponding P50 and N100 in schizophrenia, suggesting that NMDA receptor dysfunction may not underlie abnormalities of these components in schizophrenia. However, the effects of ketamine on the mouse P80 were consistent with P200 ERP changes in schizophrenia and support the hypothesis that NMDA dysfunction may contribute to some neuronal abnormalities in schizophrenia. The current study lays the groundwork for defining the role of NMDA-mediated transmission for specific aspects of neuronal processing that vary with genetic background. Future studies could use transcription profiling to clarify such interactions between genetic background, specific neuronal circuits, and transmitter systems.

Parvalbumin Cell Ablation of NMDA-R1 Causes Increased Resting Network Excitability with Associated Social and Self-Care Deficits

NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative-symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox-driven ablation of NR1 on PV-containing interneurons. In addition, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-methyl-6-(phenylethynyl) pyridine (MPEP)). The data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long-term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated before and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggest that MPEP may be beneficial for core features of autism spectrum disorders, current data suggest that such effects require intact function of NMDAR on PV interneurons.

Effects of chronic olanzapine and haloperidol differ on the mouse N1 auditory evoked potential.

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.

Effects of Nicotine Vary Across Two Auditory Evoked Potentials in the Mouse

BACKGROUND Schizophrenia patients display sensory processing deficits, reduced alpha7-nicotine receptor expression, and increased incidence of smoking, prompting investigation of nicotine receptor agonists as possible treatments. We evaluated the effects of acute and chronic nicotine, using an animal model that incorporates genetic variation for sensory processing and nicotine sensitivity. METHODS C57BL/6J and DBA/2Hsd mice received 2 weeks of 4.2 mg/kg chronic nicotine or saline. Auditory evoked potentials were recorded before and after acute nicotine injection of 1.05 mg/kg on day 14, with a paired-click paradigm (S1/S2). Amplitude and gating of the P20 and N40 were compared between conditions. RESULTS Acute nicotine increased the amplitude and gating of the P20 and decreased the amplitude and gating of the N40 across all groups, primarily by acting on S1. Chronic nicotine attenuated the effects of acute nicotine on the N40. CONCLUSIONS Our data support the notion that the mouse P20 shares pharmacological response properties with the human P50. In addition, findings suggest that nicotine might increase the initial sensory response (S1), with a resulting improvement in gating of some components.

Inhibition of auditory evoked potentials and prepulse inhibition of startle in DBA/2J and DBA/2Hsd inbred mouse substrains

Previous data have shown differences among inbred mouse strains in sensory gating of auditory evoked potentials, prepulse inhibition (PPI) of startle, and startle amplitude. These measures of sensory and sensorimotor gating have both been proposed as models for genetic determinants of sensory processing abnormalities in patients with schizophrenia and their first-degree relatives. Data from our laboratory suggest that auditory evoked potentials of DBA/2J mice differ from those previously described for DBA/2Hsd. Therefore, we compared evoked potentials and PPI in these two closely related substrains based on the hypothesis that any observed endophenotypic differences are more likely to distinguish relevant from incidental genetic heterogeneity than similar approaches using inbred strains that vary across the entire genome. We found that DBA/2Hsd substrain exhibited reduced inhibition of evoked potentials and reduced startle relative to the DBA/2J substrain without alterations in auditory sensitivity, amplitude of evoked potentials or PPI of startle. These results suggest that gating of auditory evoked potentials and PPI of startle measure different aspects of neuronal function. The differences between the substrains might reflect genetic drift. Alternatively, differences could arise from different rearing environments or other non-genetic factors. Future studies will attempt to determine the cause of these differences in sensory and sensorimotor processing between these two closely related inbred mouse strains.

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.

In Vitro-In Vivo Correlations of Scalable PLGA-Risperidone Implants for the Treatment of Schizophrenia

ABSTRACTPurposeNonadherence to antipsychotic medications is a major obstacle preventing optimal outcomes for patients with schizophrenia. Extended release systems exist in the form of depot injections, but these formulations exhibit several disadvantages. To address these concerns, we previously demonstrated proof of concept for an antipsychotic implant containing risperidone and the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA).MethodsWe build upon recently published data by utilizing a scalable single-screw extrusion system for the production of PLGA-risperidone implants. Implants were composed of 40% risperidone and 60% PLGA, with varying ratios of lactide to glycolide (50:50, 65:35, 75:25 or 85:15). Risperidone release was assessed in vitro and in vivo in rats, and Level A, B and C correlations (IVIVCs) attempted for all. Bioavailability was verified with locomotor testingResultsLevel B analysis yielded the greatest correlation between in vitro and in vivo data (R2 = 0.9425), while Level C yielded the lowest (R2 = 0.8336). Although, based on qualitative results, a Level A correlation was not achieved, it did produce an R2 of 0.9261. Locomotor testing demonstrated that peak serum concentrations coincide with significant reductions in activity.ConclusionData demonstrate the applicability of our modeling system and advance long-term, implantable antipsychotics toward clinical application.

Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability.

BACKGROUND Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. METHODS In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice. RESULTS The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability. CONCLUSIONS Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.