Early postnatal development of the MDGA2+/- mouse model of synaptic dysfunction

Synaptic dysfunction underlies many neurodevelopmental disorders (NDDs). The membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) regulate synaptic development by modulating neurexin–neuroligin complex formation. Since understanding the neurodevelopmental profile and the sex-based differences in the manifestation of the symptoms of NDDs is important for their early diagnosis, we tested a mouse model haploinsufficient for MDGA2 (MDGA2+/-) on a neurodevelopmental test battery, containing sensory, motor, and cognitive measures, as well as ultrasonic vocalizations. When male and female MDGA2+/- and wildtype (WT) C57BL/6 J mice were examined from 2 to 23 days of age using this test battery, genotype and sex differences in body weight, sensory-motor processes, and ultrasonic vocalizations were observed. The auditory startle reflex appeared earlier in the MDGA2+/- than in WT mice and the MDGA2+/- mice produced fewer ultrasonic vocalizations. The MDGA2+/- mice showed reduced locomotion and rearing than WT mice in the open field after 17 days of age and spent less time investigating a novel object than WT mice at 21 days of age. Female MDGA2+/- mice weighed less than WT females and showed lower grip strength, indicating a delay in sensory-motor development in MDGA2+/- mice, which appears to be more pronounced in females than males. The behavioural phenotypes resulting from MDGA2 haploinsufficiency suggests that it shows delayed development of motor behaviour, grip strength and exploratory behaviour, non-social phenotypes of NDDs.

突触功能障碍是多种神经发育障碍（NDDs）的核心病理机制。含膜相关粘蛋白结构域的糖基磷脂酰肌醇锚定蛋白（MDGAs）可通过调控神经连接蛋白-神经配蛋白复合物的形成，参与突触发育的调控过程。鉴于明确神经发育特征以及神经发育障碍症状表现的性别差异对其早期诊断具有重要意义，本研究针对MDGA2单倍体不足型小鼠（MDGA2+/-）开展了神经发育测试组合实验，该测试组合涵盖感觉、运动、认知相关指标以及超声发声检测。研究人员于小鼠出生后2至23日龄期间，对雄性、雌性MDGA2+/-小鼠及野生型（WT）C57BL/6J小鼠进行了上述测试，结果显示小鼠基因型与性别在体重、感觉运动功能以及超声发声方面均存在显著差异。具体而言，MDGA2+/-小鼠的听觉惊反射出现时间早于WT小鼠，且其超声发声频次显著低于WT小鼠。出生17日龄后，MDGA2+/-小鼠在旷场实验中的自主活动与直立探索行为均弱于WT小鼠；而在21日龄时，MDGA2+/-小鼠对新物体的探索时长亦显著短于WT小鼠。此外，雌性MDGA2+/-小鼠的体重低于同性别WT小鼠，且握力水平更低，这表明MDGA2单倍体不足会导致小鼠感觉运动发育延迟，且该发育缺陷在雌性个体中表现更为显著。MDGA2单倍体不足所引发的行为表型提示，该基因杂合缺失会导致小鼠运动行为、握力与探索行为的发育延迟，上述表型均属于神经发育障碍的非社会性行为表型。