Adolescent Isolation Interacts With DISC1 Point Mutation To Impair Adult Social Memory And Synaptic Functions In The Hippocampus

Disrupted-in-schizophrenia 1(DISC1)is a strong candidate susceptibility gene for a spectrum of neuropsychiatric diseases including schizophrenia,bipolar disorder and major depression,all of which are thought to result from interactions between genes and environmental risk factors such as influenza,trauma and stress.Adolescence is a sensitive period of neurodevelopment associated with plasticity-driven organization of neural circuits in multiple brain regions,including the perfrontal cortex,hippocampus and amygdala.Besides perinatal immune activation,adverse experiences during adolescent have also been proved to influence postnatal brain maturation and increase risk for stress-related mental illness in adulthood.In particular,social stress during adolescence are central features for neuropsychiatric disorders including depression,anxiety,schizophrenia and addiction.Adolescence is a key period for susceptibility to stress and stress-related mental illnesses.In previous study,we found that although DISC1 L100 P point mutation mice shows object recognition deficits,their sociability and social memory are relative normal.Therefore,we sought to investigate whether the interactions between adolescent stress and DISC1 L100 P point mutation affect adult social memory,and to explore the underlying mechanisms.1.Adolescent isolation specifically impaired social memory of adult DISC1 L100 P mice,but had no effect on WT littermates.L100P-iso mice exhibited profound deficits in social novelty preference test compared to the other three groups(WT,WT-iso and L100P): they interacted with the stranger similarly as with the familiar.2.Adolescent isolation did not increase anxiety or depression in adult DISC1L100 P mice.The four groups mice spent similar time in open arms and the total immobility time in force-swimming test.3.Adolescent isolation exacerbated adult neurogenesis deficit in L100 P mice,but had no effect on WT mice.Adolescence and DISC1 L100 P mutation play a synergistic role to impair both proliferation and neuronal differentiation process of adult neurogenesis,no affect neuronal maturation.4.Adolescent isolation caused long lasting changes of synaptic transmission in hippocampal networks of L100 P mice.Adolescent isolation causes or worsens deficit in inhibitory synaptic activity onto both DG granule cells and CA1 pyramidal neurons in hippocampal microcircuits,abnormal excitatory synaptic activity onto DG granule cells and reflect a decrease in the AMPA-mediated response and/or an increase in theNMDAR-mediated response triggered.Those results may underlie social memory deficit in adult L00P-iso mice.5.Adolescent isolation caused long lasting changes of synaptic plasticity in hippocampal network.The impaired LTP observed in CA1 of WT-iso and L100P-iso mice were mainly caused by post-synaptic mechanisms,and both pre-and post-synaptic mechanisms may underlie the LTP deficits observed in L100 P mutants.In summary,we identified here the specific interactions between genetic mutation(DISC1 L100P)and adolescence social stress that damage synaptic transmissions and social memory in adult hippocampal circuits.