Aberrant high frequency oscillations recorded in the rat nucleus accumbens in the methylazoxymethanol acetate neurodevelopmental model of schizophrenia (original) (raw)
Related papers
Pathophysiology and animal models of schizophrenia
Annals of the Academy of Medicine, Singapore, 2009
Animal models of schizophrenia are important for research aimed at developing improved pharmacotherapies. In particular, the cognitive deficits of schizophrenia remain largely refractory to current medications and there is a need for improved medications. We discuss the pathophysiology of schizophrenia and in particular the possible mechanisms underlying the cognitive deficits. We review the current animal models of schizophrenia and discuss the extent to which they meet the need for models reflecting the various domains of the symptomatology of schizophrenia, including positive symptoms, negative symptoms and cognitive symptoms.
Electrophysiological alterations in a complex rat model of schizophrenia
Behavioural Brain Research, 2016
h i g h l i g h t s • EEG phenotype characterization in a rat substrain related to schizophrenia/autism. • ERPs showed significant changes in P2 latency and N1 amplitude. • Acute ketamine treatment did not cause alterations in ERPs. • Altered power of oscillations in different frequency bands was observed. • Ketamine caused strain-dependent changes in the power of oscillations.
Emerging principles of altered neural circuitry in schizophrenia
Brain Research Reviews, 2000
This paper presents an overview of recent microscopic studies that have sought to define how limbic circuitry may be altered in postmortem schizophrenic brain. The discussion is organized around several basic questions regarding the manner in which interconnections within and between the anterior cingulate cortex and hippocampal formation and involving the glutamate, GABA and dopamine systems may contribute to the pathophysiology of this disorder. The answers to these questions are used to derive several conclusions. regarding circuitry changes in schizophrenia: 1 Schizophrenia is not a 'typical' degenerative disorder, but rather it is one in which. excitotoxicity may contribute to neuronal pathology, whether or not cell death occurs; 2 Three or more neurotransmitter systems may be. simultaneously altered within a single microcircuit; 3 Each transmitter system may show circuitry changes in more than one region, but. such changes may vary on a region-by-region basis; 4 The pathophysiology of schizophrenia may involve 'mis-wirings' in intrinsic Ž. circuits microcircuitry within a given region, but significant changes are probably also present at the level of interconnections between Ž. . two or more regions within a network macrocircuitry ; 5 While some microscopic findings appear to be selectively present in. schizophrenia and be related to a susceptibility gene for this disorder, others may also be present in patients with bipolar disorder; 6 Although some of the circuitry changes seen in schizophrenia and bipolar disorder seem to be associated with neuroleptic exposure, most. are not and may reflect the influence of non-specific environmental factors such as pre-andror postnatal stress; 7 Normal postnatal changes at the level of both macro-and microcircuitry within the limbic system may serve as 'triggers' for the onset of schizophrenia during adolescence. Taken together, these emerging principles can provide a framework for future postmortem studies of schizophrenic brain.
Mice with reduced NMDA receptor expression display behaviors related to schizophrenia
Cell, 1999
Schizophrenia is characterized by episodic positive symptoms such as delusions, hallucinations, paranoia, N-methyl-D-aspartate receptors (NMDARs) represent and psychosis and/or persistent negative symptoms a subclass of glutamate receptors that play a critical such as flattened affect, impaired attention, social withrole in neuronal development and physiology. We redrawal, and cognitive impairments (Ban et al., 1984). A port here the generation of mice expressing only 5% of major explanatory hypothesis for the pathophysiology normal levels of the essential NMDAR1 (NR1) subunit. of schizophrenia is the dopamine hypothesis, which Unlike NR1 null mice, these mice survive to adulthood maintains that dysfunction of the dopamine neurotransand display behavioral abnormalities, including inmitter system underlies the behavioral abnormalities creased motor activity and stereotypy and deficits in that accompany schizophrenia. This hypothesis is based social and sexual interactions. These behavioral alteron the observation that drugs effective in treating ations are similar to those observed in pharmacologischizophrenia share the common feature of blocking cally induced animal models of schizophrenia and can dopamine receptors (Anden et al., 1970; Seeman et al., be ameliorated by treatment with haloperidol or clo-1976). In many respects the behavior of patients with zapine, antipsychotic drugs that antagonize dopaminschizophrenia is consistent with elevated levels of dopaergic and serotonergic receptors. These findings supminergic neurotransmission, and some of the symptoms port a model in which reduced NMDA receptor activity of schizophrenia can be reproduced by drugs such as results in schizophrenic-like behavior and reveals how amphetamine that increase dopaminergic tone (Griffith pharmacological manipulation of monoaminergic pathet al., 1972; Angrist et al., 1974). However, altered levels ways can affect this phenotype. of dopamine or dopamine receptors have not generally been observed upon postmortem examination of the brains of schizophrenic patients (Knable et al., 1994; Introduction Lahti et al., 1996; Carlsson et al., 1997). An alternate explanation for the etiology of schizo-NMDA receptors, together with AMPA and kainate rephrenia is the glutamate dysfunction hypothesis. This ceptors, comprise the known ionotropic glutamate rehypothesis originated from the observation that phencyceptors (Nakanishi et al, 1998). NMDA receptors have clidine (PCP) intoxication closely mimics schizophrenia generated considerable interest due to their unique (Luby et al., 1959). At serum levels that produce schizopharmacological and electrophysiological properties phrenic symptoms, PCP acts as a noncompetitive anand their role in synapse refinement, neuronal plasticity, tagonist of NMDA receptors (Javitt and Zukin, 1991). and excitotoxicity (Nakanishi et al., 1998). These recep-Ketamine and MK-801, two additional noncompetitive tors require concurrent membrane depolarization and antagonists of NMDA receptors, also produce schizoglutamate binding for activation. Under these condiphrenic symptoms (Ellison, 1995; Malhotra et al., 1997; tions, Ca 2ϩ influx through the NMDA receptor channel Abi-Saab et al., 1998) and exacerbate symptoms in paprovides a second messenger system linking synaptic tients with schizophrenia (Javitt and Zukin, 1991). These activity to long-term changes in synaptic efficacy (Nafindings led to the use of PCP-and MK-801-treated kanishi et al., 1998). Functional NMDA receptors are animals as models for schizophrenia (Carlsson and composed of a common NR1 subunit and one of four Carlsson, 1990; Corbett et al., 1993, 1995). NR2 subunits (NR2A-NR2D) combined in an undeter-The glutamate dysfunction hypothesis is not inconsismined ratio to make the heteromeric receptor complex tent with an important role for dopamine in the patho-(Kutsuwada et al., 1992; Monyer et al., 1992). An inhibitory NR3 subunit may also be present in the receptor genesis of this disease or with the current therapeutic complex, particularly during development (Das et al., approach for schizophrenia, which relies on drugs that 1998). act through dopamine receptor blockade or the combined antagonism of dopamine and serotonin receptors (Meltzer, 1991
Review of Experimental Models of Schizophrenia
International Neuropsychiatric Disease Journal, 2023
Schizophrenia is a severe psychiatric disease that has a lifetime prevalence of 1% in most of the populations studied. The neuropathology and psychopathology of Schizophrenia are still poorly understood. This is attributed to the paucity of adequate animal models. Schizophrenia is a disorder of the human brain. Consequently, the potency of animal models in Schizophrenia research is limited to certain aspects of the disease. One of the most difficult aspects of modelling Schizophrenia in animals has been the lack of a clear and explicit conceptual framework for this disorder. This review discussed drug-induced animal models of Schizophrenia such as Ketamine (NMDA receptor antagonist), Phencyclidine (NMDA receptor antagonist) etc. It also discussed genetic animal models of Schizophrenia which include but not limited to Schizophrenia susceptibility Genes, Neuregulin-1(NRG1), DAT gene, Zinc finger DHH-type3 containing 8
Animal Models of Schizophrenia
Current Topics in Behavioral Neurosciences, 2010
Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy. All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein. Most rodent models have behavioural phenotype changes that resemble 'positive-like' symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively. The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy. The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them. More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks. The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms. Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed.
Contribution of nonprimate animal models in understanding the etiology of schizophrenia
Journal of Psychiatry & Neuroscience, 2011
Schizophrenia is a severe psychiatric disorder that is characterized by positive and negative symptoms and cognitive impairments. The etiology of the disorder is complex, and it is thought to follow a multifactorial threshold model of inheritance with genetic and neurodevelop mental contributions to risk. Human studies are particularly useful in capturing the richness of the phenotype, but they are often limited to the use of correlational approaches. By assessing behavioural abnormalities in both humans and rodents, nonprimate animal models of schizophrenia provide unique insight into the etiology and mechanisms of the disorder. This review discusses the phenomenology and etiology of schizophrenia and the contribution of current nonprimate animal models with an emphasis on how research with models of neuro transmitter dysregulation, environmental risk factors, neurodevelopmental disruption and genetic risk factors can complement the literature on schizophrenia in humans.
Assessment of NMDA receptor NR1 subunit hypofunction in mice as a model for schizophrenia
Genes, Brain and Behavior, 2009
N-methyl-D-aspartate receptors (NMDAR) play a pivotal role in excitatory neurotransmission, synaptic plasticity, and brain development. Clinical and experimental evidence suggests a dysregulation of NMDAR function and glutamatergic pathways in the pathophysiology of schizophrenia. We evaluated electrophysiological and behavioral properties of NMDAR deficiency utilizing mice that express of only 5-10% of the normal level of NMDAR NR1-subunit. Auditory and visual event related potentials yielded significantly increased amplitudes for the P20 and N40 components in NMDAR deficient (NR1 neo -/-) mice suggesting decreased inhibitory tone. Compared to wildtypes, NR1 neo -/-mice spent less time in social interactions and demonstrated reduced nest building. NR1 neo -/-mice displayed a preference for open arms of a zero-maze and central zone of an open field, possibly reflecting decreased anxiety-related behavioral inhibition. However, locomotor activity did not differ between groups in either home cage environment or during behavioural testing. NR1 neo -/-mice displayed hyperactivity only when placed in a large unfamiliar environment, suggesting that neither increased anxiety nor nonspecific motor activation accounts for differential behavioral patterns. Data suggest that NMDAR NR1 deficiency causes disinhibition in sensory processing, as well as reduced behavioral inhibition and impaired social interactions. The behavioral signature in NR1 neo -/-mice supports the impact of impaired NMDARfunction in a mouse model with possible relevance to negative symptoms in schizophrenia.