ZBTB18/RP58 (OMIM *608433) is one of the pivotal genes responsible for 1q43q44 microdeletion syndrome (OMIM #612337) and its haploinsufficiency induces intellectual disability. However, the underlying pathological mechanism of ZBTB18/RP58 haploinsufficiency is unknown. In this study, we generated ZBTB18/RP58 heterozygous mice and found that these mutant mice exhibit multiple behavioral deficits, including impairment in motor learning, working memory, and memory flexibility, which are related to behaviors in people with intellectual disabilities, and show no gross abnormalities in their cytoarchitectures but dysplasia of the corpus callosum, which has been reported in certain population of patients with ZBTB18 haploinsufficiency as well as in those with 1q43q44 microdeletion syndrome, indicating that these mutant mice are a novel model of ZBTB18/RP58 haploinsufficiency, which reflects heterozygotic ZBTB18 missense, truncating variants and some phenotypes of 1q43q44 microdeletion syndrome based on ZBTB18/RP58 haploinsufficiency. Furthermore, these mice show glutamatergic synaptic dysfunctions, including a reduced glutamate receptor expression, altered properties of NMDA receptor-mediated synaptic responses, a decreased saturation level of long-term potentiation of excitatory synaptic transmission, and distinct morphological characteristics of the thick-type spines. Therefore, these results suggest that ZBTB18/RP58 haploinsufficiency leads to impaired excitatory synaptic maturation, which in turn results in cognitive dysfunction in ZBTB18 haploinsufficiency.

ZBTB18/RP58 (OMIM *608433) 是导致 1q43q44 微缺失综合征 (OMIM #612337) 的关键基因之一，其单倍体不足会导致智力障碍。然而， ZBTB18/RP58单倍体不足的潜在病理机制尚不清楚。在这项研究中，我们生成了ZBTB18/RP58杂合子小鼠，发现这些突变小鼠表现出多种行为缺陷，包括运动学习、工作记忆和记忆灵活性受损，这些与智障人士的行为有关，并且没有表现出明显的行为缺陷。其细胞结构异常，但胼胝体发育不良，在某些ZBTB18单倍体不足患者群体以及 1q43q44 微缺失综合征患者中已有报道，表明这些突变小鼠是ZBTB18/RP58单倍体不足的新模型，这反映了基于ZBTB18/RP58单倍体不足的杂合ZBTB18错义、截短变异和 1q43q44 微缺失综合征的一些表型。此外，这些小鼠表现出谷氨酸突触功能障碍，包括谷氨酸受体表达减少、NMDA受体介导的突触反应特性改变、兴奋性突触传递长期增强的饱和水平降低以及粗型棘的独特形态特征。因此，这些结果表明ZBTB18/RP58单倍体不足导致兴奋性突触成熟受损，进而导致ZBTB18单倍体不足的认知功能障碍。