Several lines of genetically modified mice, in which the expression of oligodendrocyte/myelin related genes has been modified, show altered behaviors relevant to schizophrenia.
Schizophrenia is characterized by three symptom clusters, positive, negative and cognitive. The positive symptoms refer to hallucinations, delusions and disorganized speech/thinking, the negative symptoms refer to social withdrawal, avolition (lack of motivation), anhedonia, and blunted affect, and the cognitive symptoms refer to deficits in attention, working memory, and executive function. To understand how genetic/molecular changes lead to schizophrenia, animal models in which molecules of interest are manipulated have been used. Although it is quite challenging to reproduce schizophrenic symptoms in rodents, especially positive symptoms, several behavioral paradigms have been developed and widely used (). Also, based on the findings that some psychostimulants, such as MK-801, ketamine, and amphetamine, could exacerbate the symptoms of schizophrenia (Tamminga and Holcomb 2005
), sensitivity to these drugs has frequently been examined in these animals.
Behaviroal models mimic psychotic symptoms of schizophrenia.
Using these behavioral paradigms, several mouse models where oligodendrocyte/myelin related genes are genetically modified have been examined, and accumulating evidence suggests that oligodendrocyte/myelin dysfunction leads to behavioral changes relevant to schizophrenia (see for a summary of animal models for schizophrenia based on the oligodendrocyte/myelin hypothesis). It should be noted that most of these animal models do not show comprehensive deficits spanning all symptomatic domains.
Animal models for schizophrenia based on oligodendrocyte/myelin hypothesis
A myelin-related mouse model for schizophrenia is NRG1+/−
mice (Stefansson et al 2002
). In these mice, researchers found hyperactivity in NRG1
+/− and ERBB4
+/−, and prepulse inhibition (PPI) deficit in NRG1
+/−. Remarkably, these changes could be reversed by the antipsychotic clozapine. DN-ERBB4 mice also showed hyperactivity and increased sensitization to amphetamine (Roy et al 2007
). Consistent with molecular evidence that RPTPβ inhibits NRG1 signaling (Buxbaum et al 2008
), mice over-expressing RPTPβ showed a similar phenotype as that observed in NRG1
+/−, including PPI deficits and hyperactivity (Takahashi et al unpublished data).
Mice lacking the Nogo-66 receptor displayed reduced working memory function (Budel et al 2008
) and locomotor activity (Hsu et al 2007
). Bace1-null mice exhibited deficits in PPI, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with Clozapine, (Savonenko et al 2008
). Further, mice over-expressing Plp1 showed reduced PPI, spatial learning and working memory deficits (Tanaka et al 2009
Cuprizone treated mice are a relatively new animal model for schizophrenia. Mice treated with Cuprizone, a neurotoxin known to induce demyelination, showed deficits in working memory, implicated in the pathophysiology of schizophrenia (Xiao et al 2008
). Varying duration of Cuprizone treatment induces different phenotypes. For instance, mice exposed to Cuprizone for 2 and 3 weeks displayed more climbing behavior and lower PPI, but mice exposed to Cuprizone for 4 to 6 weeks had less social interaction, even though both Cuprizone treated groups showed consistent brain demyelination, myelin break down, and loss of oligodendrocytes (Xu et al 2009
). A spatial working memory impairment in Cuprizone treated mice was found at all time points. Demyelination in the juvenile period had a more profound effect on working memory and social interaction at later stage of their life (Makinodan et al 2009
). Similarly, lysophosphatidylcholine, a potent demyelinating agent, injected into the ventral hippocampus of the 10-day-old rat caused deficits in PPI, motor hyperactivity in response to methamphetamine and anxiety-related behaviors (Makinodan et al 2008
). These data suggest that the timing and duration of demyelination affect the development of schizophrenia and disease severity.
In conclusion, altered expression and function of oligodendrocyte and myelin display behavioral changes relevant to schizophrenia in mice, and some of them possess enough validity of animal models for schizophrenia.