從基因模型及腦部毀除模型探討小鼠上類精神分裂症的行為表現型： Neuregulin 1 與杏仁核所扮演的角色

Abstract

Neuregulin1 (Nrg 1)是精神分裂症的可能致病基因之一，因此Nrg 1基因剔除鼠常被 用來當作研究精神分裂症的動物模型 。先前研究指出Nrg 1基因剔除鼠杏仁核有萎縮及活動異常的情況 。本研究企圖釐清Nrg 1基因缺陷與杏仁核功能異常間的關係是否與小鼠上類精神分裂症的行為表現型相關。首先，我們採用一連串的行為作業來檢驗Nrg 1基因剔除鼠是否有類精神分裂症的行為表現型，結果指出Nrg 1基因剔除鼠的前顫制、嫌惡學習、區辨能力以及基礎活動力皆有異常，而給予典型抗精神分裂症藥物(haloperidol)皆能減緩Nrg 1基因剔除鼠前顫抑制異常的程度。此外，公鼠與母鼠在為表現上有明顯的性別差異，公鼠較易受到Nrg 1基因缺損的影響產生行為上的缺陷，且 對於藥物治療的反應較差。為了進一步釐清杏仁核異常在其中所扮演的角色，我們以C57/B6小鼠作為受試者並毀除其腹側杏仁核，探討腹側杏仁核受損對前顫抑制表現的影響及抗精神分裂症藥物的治療效果。結果發現毀除腹側杏仁核會使動物前顫抑制表現變差，而於前額葉皮質內注射D1受體的共同致效劑（SKF38393）或D2受體的拮抗劑（haloperidol）皆能使顫抑制能力恢復正常。本研究證實Nrg 1基因受損及毀除腹杏 仁核皆會損害前顫抑制的表現，而於週邊或前額葉皮質給予haloperidol皆能舒緩動異 常的行為表現。綜合以上發現，我們認為精神分裂症的可能致病基因Nrg 1對動物的行為表現所造成的影響可能是透過杏仁核的作用。

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.