Dlgap2 基因突變鼠呈現加劇的攻擊行為與眶額皮質損壞

Abstract

神經突觸是大腦中極為精緻的構造，也是神經細胞異於其他細胞型態的關鍵之處。數以百億計的神經元透過它進行傳遞、轉換、與整合訊息，創造了我們栩栩如生的心智生活。近年來，許多大規模的人類基因體研究指出：神經突觸蛋白的基因突變會造成大腦社會認知功能的異常。在神經突觸中有一個特化的區域稱為突觸後緊密物質(postsynaptic density)，許多重要的突觸蛋白聚集在此，對大腦的功能有關鍵的影響。DLGAP2身為其中一個重要的蛋白質分子，許多人類基因體研究皆明確指出，它在自閉症光譜症(Autism Spectrum Disorders)中舉足輕重。因此，我們製作了Dlgap2基因突變的實驗鼠，並且發現它有嚴重、加劇的攻擊行為。眶額皮質(orbitofrontal cortex)是調節暴力行為的一個重要腦區，我們透過一系列的生化、電生理、電子顯微鏡分析，發現該基因突變鼠在眶額皮質有嚴重的突觸結構、功能失常。我們的研究清晰地指出Dlgap2在社會行為與額眶皮質的功能上皆扮演關鍵的角色。

As the elegant structures designed for neural communication, synapses are the building bricks of our mental functions. Recently, many human clinical studies point out genetic mutations in synaptic proteins may lead to dysfunctions of social cognition. Dlgap2/Sapap2, as one of the main components of scaffold proteins in postsynaptic density (PSD), has been shown to play a critical role in autism spectrum disorders (ASD). We generated Dlgap2-/- mice and discovered that they displayed exacerbated aggression in the resident-intruder paradigm and elevated social dominance in the tube test. With biochemical, ultra-structural, and electrophysiological analyses, Dlgap2-/- mice exhibited synaptic deficits in orbitofrontal cortex (OFC), a brain region recognized as a negative regulator of aggressive behaviors. Our findings clearly demonstrate that Dlgap2 plays vital roles in social behaviors of murine and proper synaptic functions of OFC.