Sialic acid enhanced the anti-stress capability under challenging situations by increasing synaptic transmission

In early life, sialic acid (SA) plays a crucial role in neurodevelopment and neuronal function. However, it remains unclear whether and how SA supplementation in early life promotes behavioral response to stress in adolescence. This study aimed to examine the effects and mechanisms of sialic acid on the anti-stress capability under challenging situations. In this study, C57BL/6 mice were daily supplemented with 1 μL SA solution/g body weight at the dose of 10 mg/kg/day from postnatal day (PND) 5 to 45. The anti-stress behaviors, including open field (OF), elevated plus maze (EPM), forced swimming test (FST), and tail suspension test (TST), were respectively performed at PND 46, PND 48, PND 50, and PND 52 to detect the anti-stress ability of SA. Our results showed that SA-treated mice were more active to face challenging situations. The fiber photometry experiment showed that SA promoted the excitatory neuronal response in the medial prefrontal cortex (mPFC), which was extensively interconnected to stress. Besides, electrophysiological results revealed SA enhanced synaptic transmission rather than neuronal excitability of mPFC excitatory neurons. It was also supported by the increasing spine density of mPFC excitatory neurons. At the molecular level, the SA elevated the transmitter release-related proteins of mPFC, including Synapsin 1 and vesicular glutamate transporter 1 (VGlut 1). Furthermore, SA supplementation enhanced synaptic transmission mainly by altering the kinetics of synaptic transmission. The SA supplementation enhanced the response capability to stress under challenging situations, and the enhanced synaptic transmission of mPFC excitatory neurons may be the neurological basis of active response under challenging situations. In general, our findings suggested SA supplementation in early life can promote stress resistance in adolescence.