ABSTRACT
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-NR1(neo-/-) 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 GABA(B)-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.
Subject(s)
Baclofen/pharmacology , Evoked Potentials, Auditory/genetics , Exploratory Behavior/physiology , GABA-B Receptor Agonists/pharmacology , Receptors, N-Methyl-D-Aspartate/genetics , Social Behavior , Synaptic Potentials/genetics , Animals , Autistic Disorder/physiopathology , Disease Models, Animal , Evoked Potentials, Auditory/drug effects , Evoked Potentials, Auditory/physiology , Exploratory Behavior/drug effects , Fluorobenzenes/pharmacology , In Situ Hybridization , Intellectual Disability/physiopathology , Interneurons/metabolism , Interneurons/pathology , Male , Mice , Mice, Transgenic , Parvalbumins/metabolism , Phenotype , Pyramidal Cells/metabolism , Pyramidal Cells/pathology , Receptors, N-Methyl-D-Aspartate/metabolism , Risperidone/pharmacology , Schizophrenia/physiopathology , Synaptic Potentials/drug effects , Synaptic Potentials/physiology , Triazoles/pharmacologyABSTRACT
Reduced NMDA-receptor (NMDAR) function has been implicated in the pathophysiology of neuropsychiatric disease, most strongly in schizophrenia but also recently in autism spectrum disorders (ASD). To determine the direct contribution of NMDAR dysfunction to disease phenotypes, a mouse model with constitutively reduced expression of the obligatory NR1 subunit has been developed and extensively investigated. Adult NR1(neo-/-) mice show multiple abnormal behaviors, including reduced social interactions, locomotor hyperactivity, self-injury, deficits in prepulse inhibition (PPI) and sensory hypersensitivity, among others. Whereas such phenotypes have largely been interpreted in the context of schizophrenia, these behavioral abnormalities are rather non-specific and are frequently present across models of diseases characterized by negative symptom domains. This study investigated auditory electrophysiological and behavioral paradigms relevant to autism, to determine whether NMDAR hypofunction may be more consistent with adult ASD-like phenotypes. Indeed, transgenic mice showed behavioral deficits relevant to all core ASD symptoms, including decreased social interactions, altered ultrasonic vocalizations and increased repetitive behaviors. NMDAR disruption recapitulated clinical endophenotypes including reduced PPI, auditory-evoked response N1 latency delay and reduced gamma synchrony. Auditory electrophysiological abnormalities more closely resembled those seen in clinical studies of autism than schizophrenia. These results suggest that NMDAR hypofunction may be associated with a continuum of neuropsychiatric diseases, including schizophrenia and autism. Neural synchrony abnormalities suggest an imbalance of glutamatergic and GABAergic coupling and may provide a target, along with behavioral phenotypes, for preclinical screening of novel therapeutics.
Subject(s)
Autistic Disorder/genetics , Behavior, Animal/physiology , Receptors, N-Methyl-D-Aspartate/genetics , Schizophrenia/genetics , Social Behavior , Animals , Autistic Disorder/epidemiology , Disease Models, Animal , Female , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Schizophrenia/epidemiologyABSTRACT
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.
Subject(s)
Biological Clocks/drug effects , Electroencephalography , Evoked Potentials, Auditory/drug effects , Excitatory Amino Acid Antagonists/adverse effects , Ketamine/adverse effects , Schizophrenia/chemically induced , Acoustic Stimulation/methods , Amphetamine/administration & dosage , Animals , Antipsychotic Agents/pharmacology , Central Nervous System Stimulants/administration & dosage , Disease Models, Animal , Drug Interactions , Haloperidol/pharmacology , Male , Mice , Mice, Inbred C57BL , Reaction Time/drug effects , Risperidone/pharmacology , Schizophrenia/drug therapy , Schizophrenia/physiopathologyABSTRACT
PURPOSE: Chemotherapeutic agents are known to produce persistent cognitive deficits in cancer patients. However, little progress has been made in developing animal models to explore underlying mechanisms and potential therapeutic interventions. We report an electrophysiological model of chemotherapy-induced cognitive deficits using a sensory gating paradigm, to correspond with performance in two behavioral tasks. EXPERIMENTAL DESIGN: Mice received four weekly injections of methotrexate and 5-fluorouracil. Whole-brain event-related potentials (ERPs) were recorded throughout using a paired-click paradigm. Mice underwent contextual fear conditioning (CFC) and novel-object recognition testing (NOR). RESULTS: Chemotherapy-treated animals showed significantly impaired gating 5 weeks after drug treatments began, as measured by the ratio of the first positive peak in the ERP (P1) minus the first negative peak (N1) between first and second auditory stimuli. There was no effect of drug on the amplitude of P1-N1 or latency of P1. The drug-treated animals also showed significantly increased freezing during fear conditioning and increased exploration without memory impairment during novel object recognition. CONCLUSIONS: Chemotherapy causes decreased ability to gate incoming auditory stimuli, which may underlie associated cognitive impairments. These gating deficits were associated with a hyperactive response to fear conditioning and reduced adaptation to novel objects, suggesting an additional component of emotional dysregulation. However, amplitudes and latencies of ERP components were unaffected, as was NOR performance, highlighting the subtle nature of these deficits.
