The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.

Huntington's disease (HD) is one of the few neurodegenerative diseases with a known genetic cause, knowledge that has enabled the creation of animal models using genetic manipulations that aim to recapitulate HD pathology. The study of behavioral and neuropathological phenotypes of these HD models, however, has been plagued by inconsistent results across laboratories stemming from the lack of standardized husbandry and testing conditions, in addition to the intrinsic differences between the models. We have compared different HD models using standardized conditions to identify the most robust phenotypic differences, best suited for preclinical therapeutic efficacy studies. With a battery of tests of sensory-motor function, such as the open field and prepulse inhibition tests, we replicate previous results showing a strong and progressive behavioral deficit in the R6/2 line with an average of 129 CAG repeats in a mixed CBA/J and C57BL/6J background. We present the first behavioral characterization of a new model, an R6/2 line with an average of 248 CAG repeats in a pure C57BL/6J background, which also showed a progressive and robust phenotype. The BACHD in a FVB/N background showed robust and progressive behavioral phenotype, while the YAC128 full-length model on either an FVB/N or a C57BL/6J background generally showed milder deficits. Finally, the Hdh Q111 knock-in mouse on a CD1 background showed very mild deficits. This first extensive standardized cross-characterization of several HD animal models under standardized conditions highlights several behavioral outcomes, such as hypoactivity, amenable to standardized preclinical therapeutic drug screening.

Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.dopamine ͉ erbB receptor ͉ neuregulin ͉ schizophrenia ͉ white matter N euregulin 1 (NRG1), a growth factor essential for brain development, and erbB4, one of its receptors, are genetically linked to schizophrenia and bipolar disorder (1-4). A role for NRG1-erbB receptor signaling in psychiatric diseases is also supported by studies showing that expression levels or function of NRG1, erbB3, and erbB4 are altered in patient tissues (1,4,5). Moreover, mice with reduced levels of NRG1 or erbB4 exhibit behavioral alterations relevant to mental illness (6-9). Although the evidence linking this pathway and psychiatric disorders is strong, the mechanisms by which it contributes to these diseases remain unknown. NRG1-erbB signaling is important in neurons, astrocytes, and oligodendrocytes (OLs), but the specific cell types through which altered NRG1-erbB signaling contributes to these disorders is undefined.Significant alterations in white matter are found in schizophrenia, bipolar disorder, major depression, anxiety, and obsessivecompulsive disorder (10-14), and genes expressed by OLs have been linked with some of these diseases (15, 16). Interestingly, NRG1-erbB signaling regulates OL development in vitro (17), although this has not been shown in the intact organism.To determine whether erbB signaling plays a role in CNS myelination and whether disruption of this pathway in OLs produces defects related to human psychiatric disorders, we analyzed mice in which erbB signaling in OLs is blocked by expression of a dominant negative erbB receptor (DN-erbB4) (18). We show that alterations in erbB signaling lead to changes in OL morphology, number, and function in vivo. Moreover, these transgenic (Tg) mice have increased levels of functional dopamine transporters (DAT) and D1 receptors and exhibit behavioral alterations suggestive of neuropsychiatric disorders. Together, these results indicate that altered NRG1-erbB signaling in OLs may be a potential contributor to the pathogenesis of mental illness....

Dopamine has been critically implicated in learning and motivation, although its precise role remains to be determined. In order to investigate the involvement of dopamine in learning and motivation for a food reward, we used dopamine transporter knockdown mice (DAT KD) that have chronically elevated levels of extracellular dopamine. The present study demonstrates that chronically elevated dopamine enhances tendency to work for a food reward without apparent effects on Pavlovian and operant learning for this reward. The increase in dopamine is associated with elevated levels of dynorphin and Fos B expression in the dorsal caudate-putamen and the core but not the shell subregion of the nucleus accumbens. These data suggest that motivation to work, but not learning, for a food reward appears to be under the critical influence of tonic dopaminergic activity in discrete brain areas relevant for a reward-directed behavior.