Kim Ji-Woon, Seung Hana, Kim Ki Chan, Gonzales Edson Luck T, Oh Hyun Ah, Yang Sung Min, Ko Mee Jung, Han Seol-Heui, Banerjee Sourav, Shin Chan Young
Department of Neuroscience, School of Medicine, Konkuk University, Seoul 05029, Republic of Korea; Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul 05029, Republic of Korea.
KU Open Innovation Center and IBST, Konkuk University, Seoul 05029, Republic of Korea.
Neuropharmacology. 2017 Feb;113(Pt A):71-81. doi: 10.1016/j.neuropharm.2016.09.014. Epub 2016 Sep 14.
Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD.
自闭症谱系障碍（ASD）是一种极具挑战性的发育障碍，主要特征为社交沟通缺陷和局限/重复行为这两种核心行为症状。由于该疾病存在众多风险因素且症状复杂，研究其病因过程并确定合适的治疗靶点仍是克服ASD面临的巨大挑战。在导致ASD的各种机制中，维持兴奋与抑制平衡成为调节神经回路正常功能的关键因素。有趣的是，我们之前涉及自闭症丙戊酸动物模型（VPA动物模型）的研究表明，由于谷氨酸能神经元分化增强和GABA能神经元减少，出现了兴奋-抑制失衡（E/I失衡）。在此，我们利用VPA动物模型，研究了内源性NMDA受体拮抗剂胍丁胺通过调节E/I失衡改善ASD症状的潜在作用，作为一种新型治疗候选药物。我们观察到，单次给予胍丁胺可挽救VPA动物模型中受损的社交行为以及多动和重复行为。我们还观察到，胍丁胺治疗可能通过调节因兴奋性神经回路增强导致的过度兴奋，挽救了VPA动物模型前额叶皮层和海马体中过度激活的ERK1/2信号通路。综上所述，我们的研究结果提供了实验证据，表明胍丁胺在改善ASD的VPA动物模型中类似ASD的症状方面可能具有治疗作用。
