Animal models of schizophrenia

Schizophrenia is a psycotic disorder which involves a deterioration in every-day functioning, and disorders in thought and feelings. There are several animal models which attempt to simulate the defects involved in schizophrenia. These involve altering an animal's biochemistry, phisiology or genetics to model aspects of the disorder. Animal models of schizophrenia fit into four basic categories: pharmacological models, developmental models, lesion models, or genetic models. Historically, pharmacological, or drug-induced models were the most widely used, these involved the manipulation of various neurotransmitter systems, including dopamine, glutamate, serotonin, and GABA. Lesion models arose from theories that Schizophrenia involves neurodegeneration, and that problems during neurodevelopment cause the disease.

Dopamine
In the dopamine hypothesis of schizophrenia, schizophrenia was hypothesised to be caused by disturbed dopamine neurotransmission. Dopamine is a monoamine neurotransmitter which is involved in other diseases, such as Parkinson's disease. There is evidence for increased activity of the mesolimbic pathway, a dopaminergic pathway, this comes from the discovery of incresed L-DOPA decarboxylase levels in the brains of schizophrenia patiants. L-DOPA decarboxylase is an enzyme which converts L-DOPA to dopamine by removing a carboxyl group. Amphetamine also increases activity in the mesolimbic pathway, and treatment of animals with it causes changes in behavior like hyperlocomotion and stereotypy. Drug-induced stereotypy in animal models can be reduced by treatment with antipsychotics.

Glutamate
Glutamate is the most abundant excitatory neurotransmitter in vertabrate nervous systems. Phencyclidine (PCP), which is an antagonist to glutamate NMDA receptors, mimics symptoms of non-paranoid schizophrenia in normal patients. Glutamate's interactions with dopamine may also be relevant to schizophrenia. Clozapine, an antipsycotic drug, can reduce the effects of PCP on tasks involving the prefrontal cortex.

Serotonin
Serotonin is a monoamine neurotransmitter which has been associated with schizophrenia. The psychedelic drug classes indoleamines and phenethylamines can affect serotoninergic 5-HT2A receptors. LSD, an indoleamine, affects startle habituation and prepulse inhibition of startle, which are indicators of human schizophrenia.

GABA
γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter. The GABAergic system may be involved in schizophrenia due to its interactions with the dopaminergic system. Picrotoxin, an antagonist for the GABAA receptor, produces prepulse inhibition of startle in rats. Haloperidol, an antipsychotic drug, reduces this effect.

Lesions
Studies into the neurodevelopmental and neurodegenerative aspects of schizophrenia have led to the use of lesion models to investigate these aspects. A lesion is damage to an area of tissue by any cause. The evidence for the neurodegenerative theory is a reduction in the volume of the cerebral cortex and an increase in the volumes of the ventricles (cavities in the brain containing cerebrospinal fluid) associated with schizophrenia. Most neurodegenerative diseases produce increased levels of glial cells such as astrocytes, this is not found in schizophrenia. The evidence in favour of the neurodevelopmental theory includes the connection of some physical abnormalities with schizophrenia.

Brain regions used in lesion models of schizophrenia include the prefrontal cortex, the hippocampal formation, and the thalamus. Using rats an an animal model, lesions of the prefrontal cortex have produced increased and protracted response to stress and a lower prepulse inhibition of startle when treated with apomorphine.

Developmental models
There is evidence from epidemiological studies that environmental factors during gestation or around childbirth can increase the probability of someone developing schizophrenia.

Methylazoxymethanol acetate
Methylazoxymethanol acetate (MAM) is used during gestation to affect aspects of neural development. MAM selectively targets neuroblasts in the central nervous system. As neuroblasts are cells which become neurons, interfering with them using MAM inhibits the areas of the brain which are developing most quickly. The effects of MAM therefore depend on the stage of development at which it is administered, or the gestational age of the subject. In rat studies, administration of MAM at day 17 of gestation (GD17) results in several cognitive and anatomical changes which are common to schizophrenia patients. The thickness of the hippocampus and the thalamus are reduced, the locomotor effects of amphetamines and the spontaneous firing rate of dopominergic neurons in the ventral tegmental area are increased, and defects in working spacial memory are observed.

Social isolation
Rats have a specific social organization within colonies. In social isolation models, pups which are placed in separate cages after being weaned show adult behavioral changes and altered neural development. These changes remain after being re-introduced into the colony in adulthood. The behavioral deficits caused include neophobia, a larger response to new stimulus, locomotor hyperactivity, and increased aggression. Social isolation rats' inability to habituate to new environments may be caused by an increased mesolimbic dopaminergic activity.

Genetic models
Studies involving twins have shown that schizophrenia is a heritable disease. While no one gene is responsible for the disease, a large number of possible genes have been identified. Genetic animal models of schizophrenia often involve knockout mice, where one or more of these genes is removed or disrupted in mouse models.

DISC1
Disrupted in schizophrenia 1(DISC1) was one of the first genes discovered to be involved in schizophrenia. As of 2011, seven different strains of DISC1 knockout mice had been developed. As in schizophrenia patients, DISC1 mice have an increased lateral ventricle size, reduced cortical size, changes to the hippocampus, and changes to prepulse inhibition of startle are reversed on treatment with haloperidol and clozapine.