title: Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ji-Woon
authors.initials: JW
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Hana
authors.initials: H
authors.lastname: Seung
authors.affiliation: KU Open Innovation Center and IBST, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Ki Chan
authors.initials: KC
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Edson Luck T
authors.initials: ELT
authors.lastname: Gonzales
authors.affiliation: 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.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Oh
authors.affiliation: 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.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Mee Jung
authors.initials: MJ
authors.lastname: Ko
authors.affiliation: KU Open Innovation Center and IBST, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
authors.affiliation: National Brain Research Center, NH-8, Nainwal Mode, Haryana, India.
authors.forename: Sourav
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: 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. Electronic address: chanyshin@kku.ac.kr.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
mesh_terms: D000376:Agmatine / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D006120:Grooming / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006948:Hyperkinesis / Q000517:prevention & control; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012919:Social Behavior; D014635:Valproic Acid
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D014635:Valproic Acid; D000376:Agmatine
keywords: Agmatine; Autism spectrum disorder; E/I imbalance; NMDA receptor; Therapeutics; Valproic acid