PMC:2938983 / 4561-8979 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2938983","sourcedb":"PMC","sourceid":"2938983","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2938983","text":"Modeling Major Symptom Categories of Schizophrenia in Mice\nSchizophrenia is a highly heterogeneous disorder of myriad symptoms. The presentation of different symptoms and their severity varies considerably across patients. While this complexity cannot be fully recapitulated in the mouse, specific symptom categories can be behaviorally modeled in mice. A constructive starting point has been to demarcate schizophrenia-related phenotypes into the clinical categories of positive, negative and cognitive/executive symptoms (Arguello and Gogos, 2006; Powell and Miyakawa, 2006).\nPositive symptoms are so-called because they add to the normal behavioral repertoire. While a mouse test for hallucinations has not yet been proffered, other positive symptoms, such as psychomotor agitation and hyper-responsivity to psychotomimetic drugs, can be modeled in mice by testing locomotor responses (particularly under provocative situations, such as stressful environments) (Figure 1A), and locomotor hyperactivity-inducing effects of psychostimulants (e.g., amphetamine) and other psychotomimetics [e.g., N-methyl-δ-aspartate receptor (NMDAR) antagonists dizocilpine/MK-801 or PCP; Figure 1B].\nFigure 1 Mouse behavioral assays for the major symptom categories of schizophrenia. Positive symptoms. The psychomotor agitation and hyper-responsivity to psychotomimetic drugs found in schizophrenia can be modeled in mice by testing locomotor responses in novel and stressful environments (A) and locomotor hyperactivity-inducing effects of psychotomimetics, such as NMDAR antagonists (B), respectively. Negative symptoms. Schizophrenia is often associated with blunted affect, social withdrawal, and loss of pleasure in normally rewarding activities (anhedonia). Social interactions with other mice (C) and decreased preference or motivation to obtain rewarding substances, such as sucrose (D), can be assessed as a means to model these negative symptoms. Cognitive/executive symptoms. Abnormalities in cognition and executive functions are a prominent feature of schizophrenia and range from deficits in episodic memory, poor attention and sensorimotor gating, to impaired reversal learning and set-shifting. Learning and memory can be tested in mice using, e.g., the reference memory version of the Morris water maze (E), while prepulse inhibition of the startle response provides a ready measure of sensorimotor gating (F). Rodent models of schizophrenia have traditionally focused on positive symptoms, and this has provided many important mechanistic insights and drug leads. However, there has been a growing emphasis on studying, modeling and treating the negative and cognitive/executive symptoms of the disease (Carter et al., 2008). Negative symptoms (so-called because they subtract from the normal behavioral repertoire) include blunted affect, social withdrawal and loss of pleasure in normally rewarding activities (anhedonia). Various rodent assays for social behavior and anhedonia (e.g., decreased preference or motivation to obtain rewarding substances such as sucrose) have been typically used to model other disorders, such as anxiety (File and Seth, 2003), autism (Crawley, 2004) and depression (Strekalova et al., 2004), but also lend themselves well to the study of abnormalities in these behaviors in models of schizophrenia (Figures 1C,D).\nThe category of cognitive/executive symptoms covers a range of abnormalities: from deficits in episodic memory to impaired attention and sensorimotor gating. Assays for prepulse inhibition and latent inhibition provide ready measures of sensorimotor gating and selective attention, respectively, that can be applied across species (Figure 1F). Both have been widely employed as a screen for antipsychotics and a measure of schizophrenia-related phenotypes in mutant mice (Feldon and Weiner, 1992; Geyer et al., 2001). There are also numerous very well-studied methods for testing various forms of cognition, such as the spatial reference memory version of the Morris water maze (Figure 1E). However, although impaired episodic memory is one of the strongest features of the cognitive profile of schizophrenia (Ranganath et al., 2008), rodent models of this disease have not relied upon such measures – perhaps because they do not distinguish a model of schizophrenia from other conditions that are also characterized by memory deficits, e.g., Alzheimer's disease.","divisions":[{"label":"Title","span":{"begin":0,"end":58}},{"label":"Figure caption","span":{"begin":1185,"end":2416}}],"tracks":[{"project":"TEST0","denotations":[{"id":"20859447-190-198-266763","span":{"begin":544,"end":548},"obj":"[\"17015235\"]"},{"id":"20859447-217-225-266764","span":{"begin":571,"end":575},"obj":"[\"16797265\"]"},{"id":"20859447-155-163-266765","span":{"begin":2726,"end":2730},"obj":"[\"18466880\"]"},{"id":"20859447-229-237-266766","span":{"begin":3161,"end":3165},"obj":"[\"12600701\"]"},{"id":"20859447-231-239-266767","span":{"begin":3185,"end":3189},"obj":"[\"15666335\"]"},{"id":"20859447-231-239-266768","span":{"begin":3226,"end":3230},"obj":"[\"15266352\"]"},{"id":"20859447-147-155-266769","span":{"begin":3846,"end":3850},"obj":"[\"1491358\"]"},{"id":"20859447-167-175-266770","span":{"begin":3866,"end":3870},"obj":"[\"11549216\"]"},{"id":"20859447-137-145-266771","span":{"begin":4183,"end":4187},"obj":"[\"18495087\"]"}],"attributes":[{"subj":"20859447-190-198-266763","pred":"source","obj":"TEST0"},{"subj":"20859447-217-225-266764","pred":"source","obj":"TEST0"},{"subj":"20859447-155-163-266765","pred":"source","obj":"TEST0"},{"subj":"20859447-229-237-266766","pred":"source","obj":"TEST0"},{"subj":"20859447-231-239-266767","pred":"source","obj":"TEST0"},{"subj":"20859447-231-239-266768","pred":"source","obj":"TEST0"},{"subj":"20859447-147-155-266769","pred":"source","obj":"TEST0"},{"subj":"20859447-167-175-266770","pred":"source","obj":"TEST0"},{"subj":"20859447-137-145-266771","pred":"source","obj":"TEST0"}]},{"project":"0_colil","denotations":[{"id":"20859447-17015235-266763","span":{"begin":544,"end":548},"obj":"17015235"},{"id":"20859447-16797265-266764","span":{"begin":571,"end":575},"obj":"16797265"},{"id":"20859447-18466880-266765","span":{"begin":2726,"end":2730},"obj":"18466880"},{"id":"20859447-12600701-266766","span":{"begin":3161,"end":3165},"obj":"12600701"},{"id":"20859447-15666335-266767","span":{"begin":3185,"end":3189},"obj":"15666335"},{"id":"20859447-15266352-266768","span":{"begin":3226,"end":3230},"obj":"15266352"},{"id":"20859447-1491358-266769","span":{"begin":3846,"end":3850},"obj":"1491358"},{"id":"20859447-11549216-266770","span":{"begin":3866,"end":3870},"obj":"11549216"},{"id":"20859447-18495087-266771","span":{"begin":4183,"end":4187},"obj":"18495087"}],"attributes":[{"subj":"20859447-17015235-266763","pred":"source","obj":"0_colil"},{"subj":"20859447-16797265-266764","pred":"source","obj":"0_colil"},{"subj":"20859447-18466880-266765","pred":"source","obj":"0_colil"},{"subj":"20859447-12600701-266766","pred":"source","obj":"0_colil"},{"subj":"20859447-15666335-266767","pred":"source","obj":"0_colil"},{"subj":"20859447-15266352-266768","pred":"source","obj":"0_colil"},{"subj":"20859447-1491358-266769","pred":"source","obj":"0_colil"},{"subj":"20859447-11549216-266770","pred":"source","obj":"0_colil"},{"subj":"20859447-18495087-266771","pred":"source","obj":"0_colil"}]},{"project":"2_test","denotations":[{"id":"20859447-17015235-38208204","span":{"begin":544,"end":548},"obj":"17015235"},{"id":"20859447-16797265-38208205","span":{"begin":571,"end":575},"obj":"16797265"},{"id":"20859447-18466880-38208206","span":{"begin":2726,"end":2730},"obj":"18466880"},{"id":"20859447-12600701-38208207","span":{"begin":3161,"end":3165},"obj":"12600701"},{"id":"20859447-15666335-38208208","span":{"begin":3185,"end":3189},"obj":"15666335"},{"id":"20859447-15266352-38208209","span":{"begin":3226,"end":3230},"obj":"15266352"},{"id":"20859447-1491358-38208210","span":{"begin":3846,"end":3850},"obj":"1491358"},{"id":"20859447-11549216-38208211","span":{"begin":3866,"end":3870},"obj":"11549216"},{"id":"20859447-18495087-38208212","span":{"begin":4183,"end":4187},"obj":"18495087"}],"attributes":[{"subj":"20859447-17015235-38208204","pred":"source","obj":"2_test"},{"subj":"20859447-16797265-38208205","pred":"source","obj":"2_test"},{"subj":"20859447-18466880-38208206","pred":"source","obj":"2_test"},{"subj":"20859447-12600701-38208207","pred":"source","obj":"2_test"},{"subj":"20859447-15666335-38208208","pred":"source","obj":"2_test"},{"subj":"20859447-15266352-38208209","pred":"source","obj":"2_test"},{"subj":"20859447-1491358-38208210","pred":"source","obj":"2_test"},{"subj":"20859447-11549216-38208211","pred":"source","obj":"2_test"},{"subj":"20859447-18495087-38208212","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"TEST0","color":"#939dec","default":true},{"id":"0_colil","color":"#b7ec93"},{"id":"2_test","color":"#ec93d1"}]}]}}