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Schizophrenia Disease Models

Schizophrenia is a chronic and severe mental disorder that affects approximately 1% of the population worldwide. It usually appears in early adulthood or late adolescence, and can often be a lifelong struggle, in terms of individual suffering as well as social impact.

Schizophrenia is characterized by three sets of symptoms:
• Positive symptoms (hallucinations, delusions, racing thoughts)
• Negative symptoms (apathy, lack of emotion, poor or nonexistent social functioning)
• Cognitive symptoms (disorganized thoughts, memory problems, poor concentration and difficulties in following instructions and completing tasks) that are differentially responsive to the so-called typical and atypical antipsychotic drugs.
Currently, positive symptoms of schizophrenia are usually treatable with available therapies, while negative and cognitive symptoms are largely untreatable.

Accumulated studies uncover that disruption in brain connectivity, driven primarily by a progressive reduction in dendritic spines on cortical pyramidal neurons, may represent a key triggering mechanism underlying schizophrenia pathophysiology. As shown in Figure 1, the excitatory activity of cortical pyramidal neurons (blue) is decreased in schizophrenia as a result of N-methyl-D-aspartate (NMDA) receptor hypofunction. GABAergic interneurons (green), reduce excitatory input to neurons in the mesencephalon, because of interactions with inhibitory, which will further lead to increased dopamine activity in the striatum and decreased dopamine activity in the cortex (yellow).

Figure 1. Circuit model of neuronal changes relevant to schizophrenia. (Cannon, T.D, 2015)

Schizophrenia Disease Models and Tests at Creative Animodel

Animal models of schizophrenia at Creative Animodel serve for two main purposes. First, they may be heuristic, providing a framework in which to ask questions about etiology. Second, they may be predictive, i.e., used to test potential antipsychotic treatments, since animals and humans to a large extent share similar neuro-chemistries and neuro-circuitries of the brain. Our models include but are not limited to:

Phencyclidine (PCP) induced rodent models
Non-competitive NMDA receptor antagonists, such as ketamine, PCP or MK-801, are shown to produce complex symptoms that mimic positive and negative symptoms, as well as the cognitive deficits of schizophrenia. Given that it is well established that schizophrenia is associated with dopaminergic abnormalities, Creative Animodel establishes schizophrenia models by administration of the dopamine-releasing drug, d-amphetamine in combination with the open channel NMDA receptor blocker PCP.
The MAM model
The general consensus is that MAM administration at or before gestational day (GD) 15 produces too widespread a disruption of brain morphology and behavior to provide a useful model of changes seen in schizophrenia and that GD17 MAM is the optimal strategy. The MAM model appears to have reasonable face validity for positive and cognitive symptoms, and has construct validity in terms of structural and dopaminergic changes observed.

Model Characteristics and Pharmacology Evaluation

• Behavior measurement:
> Cognitive tests: impaired acquisition of the T-maze delayed alternation, Morris water maze (MWM), novel object recognition (NOR) test
> Sensorimotor assessment: prepulse inhibition (PPI), open field test
> Social interaction tests
• Whole brain cerebellar and hippocampal volume measured by high-field MRI.
• The behavioral characteristics of models include post-pubertal onset, loss of hippocampal and cortical connectivity       and function, limbic dopamine dysregulation, cortical glutamatergic hypofunction, vulnerability to stress, abnormal       response to reward, social withdrawal and cognitive impairment.

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Figure 2. Animal model characteristics of schizophrenia. (Jones, C.A, 2011)

Our Advantages
• A comprehensive model to meet your specific needs
• Advanced equipment (such as MRI and western blot) to produce reliable data
• Professional researchers to design and conduct stable cognitive tests

Creative Animodel is dedicated to creating the most reliable animal models of schizophrenia to promote the development of potential therapeutics in clinical studies. We are the best in scientific knowledge, expertise, data quality, flexibility and personal contacts. If you have any questions, please feel free to contact us.

References:
1. Cannon, T.D. How Schizophrenia Develops: Cognitive and Brain Mechanisms Underlying Onset of Psychosis. Trends Cogn Sci. 2015, 19(12):744-56.
2. Hau, J; Schapiro, S.J. Handbook of Laboratory Animal Science, Volume II, Third Edition: Essential Principles and Practices. CRC Press. 2010.
3. Jones, C.A, Animal models of schizophrenia. British Journal of Pharmacology. 2011, 164(4): 1162-1194.

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Creative Animodel

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