Degeneration of striatal neurons and cortical atrophy are pathological characteristics of glutaric acidemia type I (GA-I), a disease characterized by accumulation of glutaric acid (GA). The mechanisms that lead to neuronal loss and cognitive impairment are still unclear. The purpose of this study was to verify if acute exposure to GA during the neonatal period is sufficient to trigger apoptotic processes and lead to learning delay in early and late period. Besides, whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Pups mice received a dose of GA (2.5 μmol/ g) or saline, 12 hs after birth, and were treated with NAC (250 mg/kg) or saline, up to 21^th day of life. Although GA exhibited deficits in the procedural and working memories in 21 and 40-day-old mice, NAC protected against cognitive impairment. In striatum and cortex, NAC prevented glial cells activation (GFAP and Iba-1), decreased NGF, Bcl-2 and NeuN, the increase of lipid peroxidation and PARP induced by GA in both ages. NAC protected against increased p75^NTR induced by GA, but not in cortex of 21-day-old mice. Thus, we showed that the integrity of striatal and cortical pathways has an important role for learning and suggested that sustained glial reactivity in neonatal period can be an initial trigger for delay of cognitive development. Furthermore, NAC protected against cognitive impairment induced by GA. This work shows that early identification of the alterations induced by GA is important to avoid future clinical complications and suggest that NAC could be an adjuvant treatment for this acidemia.

纹状体神经元的退化和皮质萎缩是戊二酸血症 I 型 (GA-I) 的病理特征，其特征是戊二酸 (GA) 的积累。导致神经元丢失和认知障碍的机制尚不清楚。本研究的目的是验证新生儿期急性暴露于 GA 是否足以触发细胞凋亡过程并导致早期和晚期学习延迟。此外，N-乙酰半胱氨酸 (NAC) 是否可以防止 GA 引起的损伤。Pups 小鼠在出生后 12 小时接受一剂 GA (2.5 μmol/g) 或生理盐水，并用 NAC (250 mg/kg) 或生理盐水治疗，直至^第21 天生命的一天。尽管 GA 在 21 天和 40 天大的小鼠中表现出程序性和工作记忆缺陷，但 NAC 可以防止认知障碍。在纹状体和皮质中，NAC 阻止神经胶质细胞激活（GFAP 和 Iba-1），减少 NGF、Bcl-2 和 NeuN，增加 GA 诱导的脂质过氧化和 PARP。NAC 可防止 p75 ^NTR升高由 GA 诱导，但不在 21 天大小鼠的皮层中。因此，我们表明纹状体和皮质通路的完整性对学习具有重要作用，并表明新生儿期持续的神经胶质反应性可能是认知发育延迟的初始触发因素。此外，NAC 可以防止 GA 引起的认知障碍。这项工作表明，早期识别 GA 引起的改变对于避免未来的临床并发症很重要，并表明 NAC 可以作为这种酸血症的辅助治疗。