ABSTRACT
The reticulon-4 receptor, encoded by RTN4R, limits axonal sprouting and neural plasticity by inhibiting the outgrowth of neurites. Human association studies have implicated mutations in RTN4R in the development of schizophrenia, including the identification of several rare nonconservative missense mutations of RTN4R in schizophrenia patients. To investigate the effects of missense mutation of the reticulon-4 receptor on phenotypes relevant to schizophrenia, we behaviourally characterized a novel Rtn4r mutant mouse line with an amino acid substitution (R189H) in the Nogo-66 binding site. Behavioural assays included prepulse inhibition of acoustic startle, locomotor activity, social interaction and spatial cognition. When compared with wildtype littermates, Rtn4r mutant mice exhibited greater social preference, which may reflect a social-anxyolitic effect, and a mild impairment in spatial cognition. Given the mild effect of the R189H mutation of Rtn4r on behavioural phenotypes relevant to schizophrenia, our results do not support missense mutation of RTN4R as a strong risk factor in the pathogenesis of schizophrenia.
Subject(s)
Interpersonal Relations , Memory Disorders/genetics , Mutation, Missense/genetics , Myelin Proteins/genetics , Receptors, Cell Surface/genetics , Acoustic Stimulation/adverse effects , Animals , Arginine/genetics , Behavior, Animal , GPI-Linked Proteins/deficiency , GPI-Linked Proteins/genetics , Histidine/genetics , Inhibition, Psychological , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/genetics , Myelin Proteins/deficiency , Nogo Receptor 1 , Receptors, Cell Surface/deficiency , Reflex, Acoustic/geneticsABSTRACT
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.
Subject(s)
Disease Models, Animal , Schizophrenia/etiology , Animals , Humans , Risk Factors , Schizophrenia/diagnosisABSTRACT
BACKGROUND: Injection of nerve growth factor (NGF) into the developing frontal cortex (FC) has been shown to produce adult-onset subcortical dopaminergic hyperactivity, impaired prepulse inhibition of the acoustic startle response, and several neuropathological features of schizophrenia. The present study was to determine whether such lesions would lead to impaired social interaction, a prominent negative feature of schizophrenia. METHODS: Rat pups received daily injections of human recombinant NGF into the developing FC on postnatal days 1 and 2 to partially lesion subplate neurons. Lesioned rats were tested in similar-treatment pairings lasting 23.5 hours using the EthoVision behavioral monitoring system at 6 and 14 weeks of age. Brains were then perfusion fixed for histological analysis. RESULTS: Lesioned rats showed significantly increased movement, relative to controls, during the light phase at 6 weeks of age. At 14 weeks, they maintained a significantly greater mean distance apart from one another, and engaged in significantly less approach and avoidance behavior during the dark phase, relative to controls. Histological changes were consistent with those described previously in this animal model. CONCLUSION: Results indicate that injections of NGF into the developing FC of neonatal rats result in reduced social interaction, which is consistent with behaviors observed in human schizophrenia patients.
Subject(s)
Disease Models, Animal , Nerve Growth Factor/pharmacology , Prefrontal Cortex/drug effects , Schizophrenia/chemically induced , Social Behavior , Age Factors , Aging , Animals , Animals, Newborn , Female , Injections , Locomotion/drug effects , Male , Nerve Growth Factor/administration & dosage , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects , Schizophrenia/physiopathologyABSTRACT
Many of the inbred mouse strains commonly used in biomedical research are homozygous for the rd1 mutation of the Pde6b gene, which causes retinal degeneration. To dissociate the behavioural effects of rd1 homozygosity from those of the genetic background of the host strain in the most widely used paradigms for evaluating the cognitive abilities of mice, two rd1 homozygous strains (C3H/HeJ and CBA/J) were compared with two Pde6b wild-type strains, each possessing a genetic background identical (C3A.BLiA-Pde6b+/J) or very similar (CBA/CaJ) to that of its rd1 homozygous relative. In the fear conditioning procedure, the presence of the rd1 mutation had no effect on performance at any stage, as the superior contextual learning of the CBA/J and CBA/CaJ strains could be explained by genetic background effects alone. In the Morris water maze, only the Pde6b wild-type C3A.BLiA-Pde6b+/J and CBA/CaJ strains were able to demonstrate spatial learning. The study thus demonstrates how retinal degeneration and genetic background have different effects in these two tests of hippocampus-dependent learning and memory.
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/genetics , Association Learning/physiology , Conditioning, Classical/physiology , Hippocampus/physiology , Maze Learning/physiology , 3',5'-Cyclic-GMP Phosphodiesterases/metabolism , Analysis of Variance , Animals , Cyclic Nucleotide Phosphodiesterases, Type 6 , Eye Proteins/genetics , Eye Proteins/physiology , Fear/physiology , Female , Genetics, Behavioral/methods , Male , Mice , Mice, Inbred C3H , Phenotype , Species Specificity , Statistics, NonparametricABSTRACT
Swiss mice are among the most commonly used outbred strains in biomedical research. Because prior knowledge of the baseline phenotypes of mouse strains will allow informed selection of strains for particular experiments, we sought to characterize the behavior of two previously untested outbred Swiss strains--NIH Swiss and Black Swiss--in the two most widely used paradigms for evaluating the cognitive abilities of mice. Unlike the C57BL/6J and C57BL/6J-Tyr(c-2J) controls, animals of both outbred Swiss strains were unable to demonstrate learning in the Morris water maze and contextual fear conditioning paradigms. A polymerase chain reaction assay revealed that all of the NIH Swiss and Black Swiss mice tested were homozygous for the recessive retinal degeneration 1 mutation of the Pde6b gene. Histological examination of NIH Swiss and Black Swiss mouse eyes confirmed the presence of retinal degeneration, which causes visual image blindness. These findings indicate that NIH Swiss and Black Swiss mice are visually im paired and thus may be unsuitable for use in some experiments.
