Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice

Deletions in the DAP12 gene in humans result in Nasu-Hakola disease, characterized by a combination of bone fractures and psychotic symptoms similar to schizophrenia, rapidly progressing to presenile dementia. However, it is not known why these disorders develop upon deficiency in DAP12, an immunoreceptor signal activator protein initially identified in the immune system. Here we show that DAP12-deficient (DAP12 (-/-)) mice develop an increased bone mass (osteopetrosis) and a reduction of myelin (hypomyelinosis) accentuated in the thalamus. In vitro osteoclast induction from DAP12(-/-) bone marrow cells yielded immature cells with attenuated bone resorption activity. Moreover, immature oligo-dendrocytes were arrested in the vicinity of the thalamus, suggesting that the primary defects in DAP12(-/-) mice are the developmental arrest of osteoclasts and oligodendrocytes. In addition, the mutant mice also showed synaptic degeneration, impaired prepulse inhibition, which is commonly observed in several neuropsychiatric diseases in humans including schizophrenia, and aberrant electrophysiological profiles in the thalami. These results provide a molecular basis for a unique combination of skeletal and psychotic characteristics of Nasu-Hakola disease as well as for schizophrenia and presenile dementia.

人类DAP12基因的缺失会导致纳苏 - 哈科拉病（Nasu - Hakola disease），其特征是骨折以及类似精神分裂症的精神症状，且会迅速发展为早老性痴呆。然而，尚不清楚为何在DAP12（一种最初在免疫系统中发现的免疫受体信号激活蛋白）缺乏时会出现这些病症。在此我们表明，DAP12基因缺陷（DAP12 (-/-)）的小鼠会出现骨量增加（骨硬化症）以及丘脑处髓鞘减少（髓鞘形成减少症）的情况加剧。从DAP12(-/-)骨髓细胞进行体外破骨细胞诱导，产生的是骨吸收活性减弱的未成熟细胞。此外，未成熟的少突胶质细胞在丘脑附近停滞，这表明DAP12(-/-)小鼠的主要缺陷是破骨细胞和少突胶质细胞的发育停滞。此外，突变小鼠还表现出突触退化、前脉冲抑制受损（这在包括精神分裂症在内的几种人类神经精神疾病中普遍存在）以及丘脑的异常电生理特征。这些结果为纳苏 - 哈科拉病以及精神分裂症和早老性痴呆的骨骼和精神特征的独特组合提供了分子基础。