Emerging therapeutic targets against ASD based on E/I imbalance hypothesis

抄録

Autism spectrum disorder (ASD) is hallmarked by two core domains of symptoms including social communication deficits and restricted, repetitive behaviors. Despite the dramatic increase in ASD diagnosis, social impairment still longs for a cure. Mainly due to the complexity of social behavior function and the heterogeneity of ASD etiology and pathophysiology, a unified theory targeting ASD is still far from its debut in the scientific community. Nonetheless, the excitatory-inhibitory neuronal imbalance (E/I imbalance) theory of ASD, especially the altered glutamatergic signaling in the brain, is gaining more support in the field and we are among those groups providing experimental evidence for this theory. For example, we found the altered glutamatergic system in the prenatal VPA exposure and CNTNAP2 KO animal models of ASD including the dysregulation of receptor expressions and altered miniature excitatory postsynaptic currents (mEPSCs). Pharmacological modulation of glutamatergic signaling using its known modulators successfully mitigated the ASD-like behavioral symptoms in experimental animals. We then turned our attention to agmatine, an endogenous neuromodulator with antagonistic effects against glutamate receptors, as a potential therapeutic candidate for ASD. Treatment of agmatine effectively modulated the ASD-like behavioral deficits in prenatally VPA-injected animals as well as in FMRP KO mice. Agmatine also normalized the hyperactivity, repetitive behaviors and seizure susceptibility of those animal models. Pharmacological approach to modulate the levels of endogenous agmatine also successfully mimicked the effects of agmatine suggesting that modulating the glutamatergic neural activity with agmatine could provide testable ASD therapeutics.