Animal model of schizophrenia
Research into the mental disorder of schizophrenia, involves multiple animal models as a tool, including in the preclinical stage of drug development.
Lesion models, in which an area of an animal's brain is damaged, arose from theories that schizophrenia involves neurodegeneration, and that problems during neurodevelopment cause the disease.
Each extreme has its limitations, with whole-syndrome modeling often failing due to the complexity and heterogeneous nature of schizophrenia, as well as difficulty translating human specific diagnostic criteria such as disorganized speech to animals.
Neither negative symptoms, such as problems with social interaction, or hippocampus-related deficits are observed in amphetamine rodent models.
Evidence that persistent PCP use and abuse in humans results in lasting deficits beyond the period of treatment has led to the suggestion that this regime in rodents may be a more accurate model of schizophrenia than acute administration.
[8] Brain regions used in lesion models of schizophrenia include the prefrontal cortex, the hippocampal formation, and the thalamus.
In rat models, lesions of the prefrontal cortex have produced increased and protracted response to stress and a lower prepulse inhibition of startle when treated with apomorphine.
[9] There is evidence from epidemiological studies that environmental factors during gestation or around childbirth can increase the probability of someone developing schizophrenia.
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 spatial memory are observed.
In social isolation models, pups which are placed in separate cages after being weaned show behavioural changes as adults and altered neural development.
The behavioural 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.
[12] The gene NRG1 codes for neuregulin 1, a growth factor which is crucial to the development of the nervous system, and to neurotransmission and formation of synapses in adults.
While mice which have two copies of (are homozygous for) a knocked out version of NRG1 do not survive, viable animal models have been developed using heterozygous or partial knockout.
Nrg1(ΔEGF)+/− mice have been shown to have social interaction problems, reduced prepulse of inhibition and greater spontaneous locomotion.
Nrg1(ΔTM)+/− mice display hyperactivity in various conditions, an effect which is reduced by the atypical antipsychotic clozapine.
[9] One naturally occurring animal model involving dysbindin, the sdy (sandy) mouse, has a number of anatomical changes compared to normal mice, including changes to the hippocampus.
In the frontal cortices, cerebellums, and hippocampi of schizophrenia patients, the amount of the protein and its messenger RNA are reduced.
