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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. Abbreviations 5-HT6, 5-hydroxytryptamine6 receptor; BDNF, brain-derived neurotrophic factor; D2, dopamine D2 receptor; DISC-1, disrupted-in-schizophrenia 1; DTNBP1, dystobrevin-binding protein 1; EGF, epidermal growth factor; GAD65, glutamic acid decarboxylase enzyme 65 kDa isoform; GAD67, glutamic acid decarboxylase enzyme 67 kDa isoform; GAT-1, GABA transporter 1; GD, gestational day; GLAST, glutamate-aspartate transporter; Ig, immunoglobulin; LPS, lipopolysaccharide; MAM, methylazoxymethanol; NAA, N-acetylaspartic acid; nAcc, nucleus accumbens; NAAG, N-acetylaspartylglutamate; NGF, nerve growth factor; NMDA, N-methyl-D-aspartic acid; NRG1, neuregulin 1; PCP, phencyclidine; PFc, prefrontal cortex; PND, postnatal day; PPI, prepulse inhibition of acoustic startle; vHip, ventral hippocampal; VTA, ventral tegmental area LINKED ARTICLES IntroductionSchizophrenia is a chronic debilitating neuropsychiatric disorder affecting approximately 1% of the population worldwide. Symptoms cluster into three categories: positive (including auditory and visual hallucinations, delusions, conceptual disorganization and thought disorder), ...

Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and ␣-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.