Effects And Mechanism Of Early Life Adversity On Brain Development And Functions

Neuronal circuits are shaped by experience during critical periods of early postnatal life.Early life adversity during critical periods has long-term effects on the individual development and increases the risk for mental disorders such as depression,anxiety and schizophrenia.Although previous research revealed certain effects and mechanisms of early adverse experiences on the adult brain,but the effects and molecular mechanisms of early life adversity on brain during critical periods remain unknown.In this study,we adopted two experimental animal models,namely neonatal anesthesia and early maternal separation to explore the effects and mechanism of early life adversity.Ketamine-xylazine(KX)induced general anesthesia on P7 neonatal mice did not directly lead to an obvious anxiety-like phenotype in adult mice;however,two mild stressors in adulthood simulateing "double-hit" senario can lead to stressor-induced anxiety behaviors in mice.We found that neonatal general anesthesia disrupted the unsilencing of AMPA-silent synapses and unsilencing-mediated LTP in the neonatal mice.Application of AMPAkine CX546 during anesthesia effectively reversed abnormal synapses unsilencing and stressor-induced anxiety-like behaviors.Next,we performed a single,prolonged maternal separation on P5 mice.We found that early maternal separation led to abnormal behaviors in adult mice including anxiety-like behavior,cognitive impairment and social defects.In addition,we also found that early maternal separation significantly reduced PKB activity in the neonatal brain.Pharmacological inhibition of PKB activity by MK2206 in neonatal mice also caused the adult behavioral abnormalities.Electrophysiology recording revealed that the developmental synapse unsilensing were disrupted in neonatal early maternal separation mice.Pharmacologically enhancement of neural PKB activity by SC79 effectively rescued disrupted developmental synapse unsilencing and LTP at neonatal age,and prevented abnormal behaviors in adult mice.Our results indicate that early life adversity may predispose individuals for psychiatric conditions via disrupting synapse unsilencing,and potentiation of neural activities during the critical periods may be an effective approach to manage adverse effects on brain development and functions.Together,our study suggest new strategies for preventing psychiatric disorders.