Exploring schizophrenia?related phenotypes in a genetic model and a brain?lesioned model in mice: The Role of Neuregulin 1 and Amygdala
Date Issued
2010
Date
2010
Author(s)
Tien, Hsin-Hua
Abstract
Neuregulin1 (Nrg 1) is a candidate gene identified for schizophrenia. Transgenic and knock-out Nrg1 mutant mice are widely adopted as an animal model for studying schizophrenia. Previous results revealed that Nrg1 heterozygous mutants showed impaired amygdala functioning. This thesis aimed to pursue a potential link between the deletion of Nrg 1 and amygdala malfunctioning in schizophrenia-related behavior. Nrg1 knock-out and wild-type mice were tested on a series of behavioral tasks for assessment of behavior implicated in schizophrenia symptoms. It was shown that Nrg 1 heterozygous mutants exhibited deficits in sensorimotor gating, conditioned fear potentiation of startle, auditory discrimination and locomotion activity. Acute challenge with a typical antipsychotic haloperidol attenuated the prepulse inhibition deficit in Nrg 1 mutants, and this effect was partially mimicked by nicotine. Sexual dimorphism was apparent in behavioral impairment or in the effect of haloperidol treatment, with the male more vulnerable to debilitative influences but less susceptible to remedy. To explore the role of amygdala in such deficits, lesions of the basolateral amygdala were made on the naive C57/B6 mice, performance in prepulse inhibition and effects of antipsychotics were tested on this model. It was found that male mice with lesions of the basolateral amygdala exhibited the same deficit in prepulse inhibition; microinfusion of the D2 receptor antagonist haloperidol into medial prefrontal cortex (mPFC) of these mice reversed the prepulse inhibition deficit and so did the D1 receptor agonist SKF38393. These findings suggest that deletion of Nrg 1 and lesions of the basolateral amygdala caused parallel deficits in prepulse inhibition. Both deficits could be ameliorated by peripheral or intra-medial prefrontal administration of haloperidol. These findings raise a hypothesis that the schizophrenia candidate gene Nrg 1 may exert its effect on behavior through an amygdala-related mechanism.
Subjects
prepulse inhibition
aversive learning
dopamine
animal model
acetylcholine
Type
thesis
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