Behavioral Phenotypes for Negative Symptoms in Animal Models of Schizophrenia

Miyamoto, Yukio; Nitta, Atsumi

doi:10.1254/jphs.14r02cr

Cited by 24 publications

(27 citation statements)

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“…The different tests assessed point to relevant and persistent bizarre behavior, severe reduction of exploratory activity, increased freezing, diminished motivation, and impaired short-term working memory. Much future work needs to be performed to determine whether the presence of exacerbated disruptive behavior, suggesting hypersensitivity to stressful situations, but reduced activity and diminished motivation have validity as negative symptoms that characterize the clinical features of the schizophrenia spectrum (59). Moreover, cognitive impairment affecting learning and memory, but also attention and executive functions, would also be compatible with cognitive clinical symptoms of schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Mutation of the 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) Substrate-Docking Site in the Developing Brain Causes Microcephaly with Abnormal Brain Morphogenesis Independently of Akt, Leading to Impaired Cognition and Disruptive Behaviors

Cordón-Barris

Pascual-Guiral

Yang

et al. 2016

Molecular and Cellular Biology

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The phosphoinositide (PI) 3-kinase/Akt signaling pathway plays essential roles during neuronal development. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) coordinates the PI 3-kinase signals by activating 23 kinases of the AGC family, including Akt. Phosphorylation of a conserved docking site in the substrate is a requisite for PDK1 to recognize, phosphorylate, and activate most of these kinases, with the exception of Akt. We exploited this differential mechanism of regulation by generating neuron-specific conditional knock-in mice expressing a mutant form of PDK1, L155E, in which the substrate-docking site binding motif, termed the PIF pocket, was disrupted. As a consequence, activation of all the PDK1 substrates tested except Akt was abolished. The mice exhibited microcephaly, altered cortical layering, and reduced circuitry, leading to cognitive deficits and exacerbated disruptive behavior combined with diminished motivation. The abnormal patterning of the adult brain arises from the reduced ability of the embryonic neurons to polarize and extend their axons, highlighting the essential roles that the PDK1 signaling beyond Akt plays in mediating the neuronal responses that regulate brain development. The phosphoinositide 3-kinase (PI3K) signaling pathway regulates cell survival, proliferation, growth, and motility, as well as metabolism, in response to extracellular signals. Class I PI3Ks phosphorylate the membrane phospholipid phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P 2 ] to generate the phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ] second messenger (1, 2). In neurons, stimulation of PI3K by neurotrophic factors, neurotransmitters, or guidance cues results in the activation of protein kinase B (PKB) (also termed Akt), the most studied downstream effector of this signaling pathway. Akt phosphorylates and inactivates a number of cellular substrates controlling different aspects of neuronal development. They include PRAS40 and TSC2, leading to mammalian TORC1 (mTORC1) activation, which in turn promotes the synthesis of selected sets of proteins involved in the differentiation program (3); glycogen synthase kinase 3 (GSK3), which regulates cytoskeleton dynamics and participates in the establishment and maintenance of neuronal polarity (4, 5); and FOXO, which promotes the expression of genes inhibiting apoptosis (6). Genetic analysis in mice has uncovered the functional significance of PI3K for brain morphology and physiology (7-10), whereas deregulation of this signaling pathway has pathophysiological consequences in human neurodevelopmental disorders, such as schizophrenia (11-13) and autism (14, 15).3-Phosphoinositide-dependent protein kinase 1 (PDK1) transduces many agonist-induced cellular responses by activating an entire set of AGC kinase family members, in addition to Akt (16). They include S6K, SGK, RSK, and protein kinase C (PKC) isoforms. Upon cell stimulation, PDK1 is enabled to phosphorylate the T loops of all these AGC kinases, resulting in their activation (17, 18).Sin...

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Section: Discussionmentioning

confidence: 99%

Mutation of the 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) Substrate-Docking Site in the Developing Brain Causes Microcephaly with Abnormal Brain Morphogenesis Independently of Akt, Leading to Impaired Cognition and Disruptive Behaviors

Cordón-Barris

Pascual-Guiral

Yang

et al. 2016

Molecular and Cellular Biology

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“…For instance, the open‐field task assesses spontaneous locomotor activity and estimates the positive symptom . The social novelty preference task and sucrose preference task investigate negative symptoms . Novel objective recognition and fear conditioning tasks are applied for the measurement of cognitive symptoms .…”

Section: Discussionmentioning

confidence: 99%

“…[25] The social novelty preference task and sucrose preference task investigate negative symptoms. [26,27] Novel objective recognition and fear conditioning tasks are applied for the measurement of cognitive symptoms. [28] In this study, increased locomotor behaviour and deficits in social novelty preference and novel object recognition behaviour were observed after the administration of MK-801, suggesting that the MK-801-induced mouse model is a useful animal model for investigating schizophrenia-like behaviour.…”

Section: Discussionmentioning

confidence: 99%

A botanical drug composed of three herbal materials attenuates the sensorimotor gating deficit and cognitive impairment induced by MK-801 in mice

Koo

Bae

Goo

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives A botanical drug derived from the ethanolic extract composed of Clematis chinensis Osbeck (Ranunculaceae), Trichosanthes kirilowii Maximowicz (Cucurbitaceae) and Prunella vulgaris Linné (Lamiaceae) has been used to ameliorate rheumatoid arthritis as an ethical drug in Korea. In our study, we investigated the effect of this herbal complex extract (HCE) on schizophrenia‐like behaviours induced by MK‐801. Methods HCE (30, 100 or 300 mg/kg, p.o) was orally administered to male ICR mice to a schizophrenia‐like animal model induced by MK‐801. We conducted an acoustic startle response task, an open‐field task, a novel object recognition task and a social novelty preference task. Key findings We found that a single administration of HCE (100 or 300 mg/kg) ameliorated MK‐801‐induced abnormal behaviours including sensorimotor gating deficits and social or object recognition memory deficits. In addition, MK‐801‐induced increases in phosphorylated Akt and GSK‐3β expression levels in the prefrontal cortex were reversed by HCE (30, 100 or 300 mg/kg). Conclusions These results imply that HCE ameliorates MK‐801‐induced dysfunctions in prepulse inhibition, social interactions and cognitive function, partly by regulating the Akt and GSK‐3β signalling pathways.

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“…Other mouse genetic models involve modified genes which code the NMDA receptor NR1 subunit [135][136][137], dysbindin [138,139], and reelin [140,141] (see [142] for review).…”

Section: Genetic Animal Models Of Szmentioning

confidence: 99%

“…According to human epidemiologic studies infection, malnutrition, or hypoxia in the fetus are the factors which can contribute to the development of SZ. In this context, neurodevelopmental animal models of this disease have been generated where the exposure to harmful prenatal factors was highly controlled [142]. Among neurodevelopmental and lesion models, the prenatal polyI:C injection model, the prenatal methylazoxymethanol acetate (MAM) injection model, the prenatal lipopolysaccharide (LPS) model, and the neonatal ventral hippocampal lesion model will be shortly characterized.…”

Section: Neurodevelopmental Models Of Szmentioning

confidence: 99%

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

et al. 2020

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Schizophrenia (SZ) is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms, and is not satisfactorily treated by current antipsychotics. Progress in understanding the basic pathomechanism of the disease has been hampered by the lack of appropriate models. In order to develop modern drugs against SZ, efficient methods to study them in in vitro and in vivo models of this disease are required. In this review a short presentation of current hypotheses and concepts of SZ is followed by a description of current progress in the field of SZ experimental models. A critical discussion of advantages and limitations of in vitro models and pharmacological, genetic, and neurodevelopmental in vivo models for positive, negative, and cognitive symptoms of the disease is provided. In particular, this review concerns the important issue of how cellular and animal systems can help to meet the challenges of modeling the disease, which fully manifests only in humans, as experimental studies of SZ in humans are limited. Next, it is emphasized that novel clinical candidates should be evaluated in animal models for treatment-resistant SZ. In conclusion, the plurality of available in vitro and in vivo models is a consequence of the complex nature of SZ, and there are extensive possibilities for their integration. Future development of more efficient antipsychotics reflecting the pleiotropy of symptoms in SZ requires the incorporation of various models into one uniting model of the multifactorial disorder and use of this model for the evaluation of new drugs.

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Behavioral Phenotypes for Negative Symptoms in Animal Models of Schizophrenia

Cited by 24 publications

References 100 publications

Mutation of the 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) Substrate-Docking Site in the Developing Brain Causes Microcephaly with Abnormal Brain Morphogenesis Independently of Akt, Leading to Impaired Cognition and Disruptive Behaviors

Mutation of the 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) Substrate-Docking Site in the Developing Brain Causes Microcephaly with Abnormal Brain Morphogenesis Independently of Akt, Leading to Impaired Cognition and Disruptive Behaviors

A botanical drug composed of three herbal materials attenuates the sensorimotor gating deficit and cognitive impairment induced by MK-801 in mice

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

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