(Ⅰ)The Study Of Antidepressant Mechanism Of L-stepholidine (Ⅱ)Functional Studies Of Novel Ion Channels

Major depressive disorder(MDD)is a common neuropsychiatric disorder characterized by low mood,feelings of despair,loss of motivation,anhedonia and cognitive impairment.Medial prefrontal cortex(mPFC)dominates cognition,decision-making,emotional control,and many other advanced features.Previous studies have demonstrated that decreased dopaminergic transmission in the mPFC is relevant to the pathogenesis of depression.l-stepholidine(l-SPD)is a natural product that have dopamine D1-like receptor(D1R)partial agonism and dopamine D2-like receptor(D2R)antagonism.Existing evidences have indicated that l-SPD could enhance mPFC function by D1R agonism in the mPFC,therefore,it could improve negative and cognitive symptoms in treatment of schizophrenia.However,by now,there is no related report on the antidepressant effects and mechanisms of l-SPD.In this study,we will focus on the antidepressant effects of l-SPD and explore the corresponding mechanisms in the mPFC.Our results showed that l-SPD exerted antidepressant-like and anti-anxiety effects on both na?ve C57 BL/6 mice and the Sprague-Dawley rat chronic unpredictable mild stress(CUMS)model of depression.Mechanism studies revealed that l-SPD could active the mTOR signaling and increase the expression levels of synaptogenesis-related proteins(such as PSD95 and synapsin I)in the mPFC,and repaired the decreased excitatory synaptic transmission mediated by protein kinase A(PKA)functional deficit in the mPFC of CUMS depression animal model.Studies in cultured primary cortical neurons suggested that l-SPD acted as a specific D1R agonist,rather than D2 antagonist,to trigger the downstream signaling of PKA/mTOR pathway,which resulted in increasing synaptogenesis-related proteins(such as,Glu R1).In addition,our electrophysiological experimental results showed that l-SPD triggered long-term synaptic potentiation(LTP)in the mPFC,which was blocked by inhibition of D1R,PKA,and mTOR,supporting that selective activation of D1R enhanced excitatory synaptic transduction in mPFC.Collectivity,the results in this study suggested that l-SPD enhanced synaptic plasticity in mPFC through the D1R-dependent PKA/mTOR signaling pathway,which may be the primary mechanism for the l-SPD-induced antidepressant-and anxiolytic-like effects.The research of this dissertation may offer new insights into the role of mesocortical dopaminergic system in antidepressant effects,and may also provide more theoretical basis for antidepressant drug discovery and development that targeting to dopaminergic system.