THAP domain-containing protein 6 (THAP6) is a member of the THAP family and contains a conserved THAP zinc-finger domain, allowing it to regulate gene expression as a transcription factor. Previous studies have shown that THAP6 may be involved in macrophage activation and transcriptional regulation related to social stimuli; however, whether THAP6 affects emotional behavior and brain tissue structure has not yet been reported. This study aims to clarify the effects of Thap6 gene deletion on emotional behaviors in mice, preliminarily explore the effects of Thap6 gene knockout on mouse brain tissue, and provide experimental evidence for revealing the potential role of THAP6 in neuropsychiatric disorders. A whole-body Thap6 knockout mouse model was generated using CRISPR/Cas9 technology. Genotyping was performed to select heterozygous Thap6 knockout (Thap6+/-; n=8) and wild-type (WT; n=10) male C57BL/6J mice as study subjects. After the mice reached adulthood, motor and balance abilities were assessed using the rotarod test; general locomotor activity and exploratory ability were evaluated using the open-field test; depression-like behaviors were assessed using the sucrose preference test and tail suspension test; anxiety-like behavior was evaluated using the elevated plus-maze test; and social behavior was assessed using the three-chamber social test. After behavioral assessments, mouse brain tissues were collected, and hematoxylin and eosin (HE) staining and Nissl staining were used to observe changes in brain microstructure and neuronal number. Behavioral results showed that, compared with WT mice, Thap6+/- mice had a significantly lower percentage of entries into the open arms in the elevated plus maze test (t=2.516, P=0.024) and a significantly higher average movement speed in the open arms (t=3.045, P=0.013). In the three-chamber social test, the sociability index (t=4.350, P<0.001) and social preference index (t=2.732, P=0.014) of Thap6+/- mice were significantly lower than those of WT mice. No statistically significant differences were observed between the 2 groups in other behavioral indicators (all P>0.05). HE staining of brain tissues showed scattered abnormal cell morphology, loose cytoplasm, and blurred nuclei in the cortex of Thap6⁺/⁻ mice; loosely arranged neurons, enlarged intercellular spaces, and extensive vacuole formation in the amygdala; disordered arrangement of cerebellar Purkinje cells, unclear boundaries, swelling and dissolution of some nuclei, and cell loss; and loss of neuronal nucleoli and partial cellular pyknosis in the substantia nigra. In the hippocampus of Thap6⁺/⁻ mice, neurons were orderly arranged, with relatively good cell morphology, a larger number of cells, and compact arrangement. Nissl staining showed that the number of neurons in the hippocampal dentate gyrus region was significantly increased in Thap6⁺/⁻ mice (U=0, P=0.029), whereas morphological abnormalities and reduced neuronal numbers were observed in the cortex, amygdala, cerebellum, and substantia nigra (all U=0, P=0.029). Thap6 gene knockout leads to anxiety-like behavior and social behavioral deficits in mice. It also causes structural abnormalities and reductions in neuronal number across multiple brain regions. This study systematically reveals, for the first time, the important role of THAP6 in the regulation of emotional and social behaviors, provides new evidence for understanding the functional differentiation of THAP family proteins in the central nervous system, and suggests that Thap6 knockout mice may serve as a novel animal model for studying neuropsychiatric disorders related to anxiety and social deficits. 目的: THAP结构域蛋白6(THAP domain-containing protein 6，THAP6)是THAP家族成员之一，含保守的THAP锌指结构域，可作为转录因子调控基因表达。既往研究表明THAP6可能参与巨噬细胞激活及社会刺激相关的转录调控，但THAP6是否影响情绪和社交行为及脑组织结构，目前未见报道。本研究旨在明确Thap6基因缺失对小鼠情绪和社交行为的影响，初步探讨Thap6基因敲除对小鼠脑组织的影响，为揭示THAP6在神经精神疾病中的潜在作用提供实验依据。方法: 采用CRISPR/Cas9技术构建Thap6基因全身敲除小鼠模型，通过基因型鉴定筛选Thap6基因敲除杂合子(Thap6+/-，n=8)和野生型(wild-type，WT;n=10)C57BL/6J雄性小鼠作为研究对象。在小鼠成年后，采用转棒实验评估运动和平衡能力，采用旷场实验评估一般活动性和探索能力，采用糖水偏好实验和悬尾实验评估抑郁样行为，采用高架十字迷宫实验评估焦虑样行为，采用三箱社交实验评估社交行为。在行为评估结束后，收集小鼠脑组织，采用苏木精-伊红(hematoxylin and eosin，HE)染色和尼氏染色观察脑组织微结构和神经元数量的改变情况。结果: 行为学结果显示，与WT小鼠相比，Thap6+/-小鼠在高架十字迷宫中进入开放臂的次数百分比显著降低(t=2.516，P=0.024)、在开放臂中的平均运动速度显著增快(t=3.045，P=0.013);在三箱社交实验中，Thap6+/-小鼠的社交能力指数 (t=4.350，P<0.001)和社交偏好指数(t=2.732，P=0.014)均显著低于WT组;其他行为实验各指标2组间的差异均无统计学意义(均P>0.05)。脑组织HE染色结果显示，Thap6+/-小鼠皮质散在细胞形态异常、细胞质疏松、细胞核模糊;杏仁核神经元排列松散、细胞间隔增大、大量空泡形成;小脑浦肯野细胞排列不齐、边界不清、部分细胞核肿胀溶解、细胞缺失;黑质神经元核仁丢失、部分细胞固缩;Thap6+/-组小鼠海马神经元排列有序，细胞形态较好，数目较多，排列紧密。尼氏染色结果显示，Thap6+/-小鼠海马齿状回区域神经元数量显著增多(U=0，P=0.029)，皮质、杏仁核、小脑、黑质4个脑区均出现形态异常和神经元数量减少(均U=0，P=0.029)。结论: Thap6基因敲除导致小鼠焦虑样行为和社交行为缺陷，同时导致小鼠多个脑区脑结构异常和神经元数量减少。本研究首次系统揭示了THAP6在情绪与社交行为调控中的重要作用，为理解THAP家族蛋白在中枢神经系统中的功能分化提供了新证据，并提示Thap6基因敲除小鼠可能作为研究焦虑和社交障碍相关神经精神疾病的新型动物模型。.
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